WO2024206673A2

WO2024206673A2 - Treatment of fgg related hearing disorders

Info

Publication number: WO2024206673A2
Application number: PCT/US2024/022037
Authority: WO
Inventors: Omri GOTTESMAN; Eric BUSS; Shannon BRUSE; Brian CAJES; David Lewis; Gregory Mcinnes; David Rozema; John VEKICH; Darren H. Wakefield
Original assignee: Empirico Inc.
Priority date: 2023-03-29
Filing date: 2024-03-28
Publication date: 2024-10-03

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets FGG. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a hearing disorder related to FGG. The method may include providing an oligonucleotide to a subject that targets FGG.

Description

TREATMENT OF FGG RELATED HEARING DISORDERS

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/455,363, filed March 29, 2023, U.S. Provisional Application No. 63/582,784, filed September 14, 2023, and U.S. Provisional Application No. 63/585,553, filed September 26, 2023, all of which applications are incorporated herein by reference in their entirety.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-749_601_SL.xml, created March 27, 2024, which is 6,429,668 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

BACKGROUND

[0003] Hearing disorders are widely abundant, and improved therapeutics are needed.

SUMMARY

[0004] Disclosed herein, in some aspects, are compositions comprising oligonucleotides target FGG. The oligonucleotide may be useful for treating an FGG-related disorder such as hearing loss or another hearing-related disorder. In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing measurement in the subject, relative to a baseline hearing measurement. In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing disorder measurement in the subject, relative to a baseline hearing disorder measurement. In some embodiments, the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise -induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss. In some embodiments, the hearing measurement or the hearing disorder measurement comprises a pure -tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions measurement.

[0005] In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2'-fluoro, 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'- O-N-methylacetamido (2'-0-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises 2’-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N- acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar comprises GalNAc. In some embodiments, the sugar moiety comprises ETL17. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length. In some embodiments, the oligonucleotide comprises a nucleoside base sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1-3484. In some embodiments, the oligonucleotide comprises the nucleoside base sequence of any one of SEQ ID NOs: 1-3484.

[0006] In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3621. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. In some embodiments, the antisense strand comprises a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. [0007] In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 3621. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, described herein is a method of treating a subject having a hearing disorder, comprising administering an effective amount of the composition described herein to the subject. In some embodiments, the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is an example of a GalNAc ligand.

[0009] FIG. 2 is an example of a GalNAc ligand.

DETAILED DESCRIPTION

[0010] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) detects associations between genetic variants and traits in a population sample, and this improves understanding of the biology of disease and provides evidence of applicable treatments. A GWAS generally utilizes genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease. Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0011] Functional annotation of variants and/or wet lab experimentation is used to identify the causal genetic variant identified via GWAS, and in many cases leads to identification of disease-causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) allows that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0012] Identification of such gene-disease associations has provided insights into disease biology and is used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients is exogenously ‘programmed’ into replicating the observation from human genetics. There are several options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, liver, brain, or neural tissue) and a relevant indication.

[0013] The fibrinogen gamma chain gene, also known as fibrinogen gamma gene (FGG), is located on chromosome 4, and encodes fibrinogen gamma chain (also referred to as FGG protein). The FGG protein may be a gamma component of fibrinogen. FGG protein may include 453 amino acids and have a mass of about 51.5 kDa. An example of a FGG amino acid sequence, and further description of FGG is included at uniprot.org under accession no. P02679 (last modified September 29, 2021). FGG may be secreted and affect hearing. FGG may be secreted by the liver cells such as hepatocytes.

[0014] Here, it is shown that genetic variants causing inactivation of FGG resulted in protective associations for hearing disorders. Therefore, inhibition of FGG may serve as a therapeutic for treatment of hearing disorders (e.g., idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss). [0015] Disclosed herein are compositions comprising an oligonucleotide that targets FGG. Where inhibition or targeting of FGG is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a FGG protein or FGG RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the FGG gene using an oligonucleotide described herein, the FGG protein may be inhibited or targeted as a result of there being less production of the FGG protein by translation of the FGG RNA; or a FGG protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a FGG RNA and reduces production of the FGG protein from the FGG RNA. Thus, targeting FGG may refer to binding a FGG RNA and reducing FGG RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

[0016] Also provided herein are methods of treating a hearing disorder or disease by providing or administering an oligonucleotide that targets FGG in a subject in need thereof. Administration of the oligonucleotide to a subject may improve hearing related traits, such as pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions.

I. COMPOSITIONS

[0017] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets FGG. In some embodiments, the composition consists of an oligonucleotide that targets FGG. In some embodiments, the oligonucleotide reduces FGG mRNA expression in the subject. In some embodiments, the oligonucleotide reduces FGG protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder (e.g., hearing disorder) as described herein.

[0018] Some embodiments include a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA or protein levels in a cell (e.g., hepatocyte or neuron), fluid (e.g., blood, serum, plasma, or cerebrospinal fluid (CSF)), tissue (e.g., brain or liver tissue), or organ (e.g., the brain or liver).

[0019] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell (e.g., hepatocyte). In some embodiments, the cell is a neuron. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural tissue. In some embodiments, the neural tissue is CNS tissue. In some embodiments, the neural tissue is brain tissue (e.g., neuronal, glia, or endothelial tissue). In some embodiments, the fluid is CSF. In some embodiments, the FGG mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG protein levels in a cell, fluid (e.g., CSF) or tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is a neural cell (e.g., CNS cell (e.g., brain cell)). In some embodiments, the cell is a neuronal cell. In some embodiments, the cell is a glial cell. In some embodiments, the cell is an endothelial cell. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural (e.g., CNS (e.g., brain)) tissue. In some embodiments, the fluid is CSF. In some embodiments, the FGG protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount diminishes a hearing disorder or disease phenotype, such as a hearing disorder phenotype. A disorder may include a disease. The hearing disease or disorder may include hearing disorders (e.g., idiopathic sudden sensorineural hearing loss (ISSNHL), noise - induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss). For hearing indications, fibrinogen may be lowered enough to have a therapeutic effect on hearing disorders but without significantly affecting coagulation parameters such as PT or aPTT.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases a hearing disease phenotype. The hearing disease phenotype may include a pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions. In some embodiments, the hearing disease phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the hearing disease phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount increases hearing (e.g., as determined by a hearing measurement). In some embodiments, the hearing is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hearing is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hearing is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the hearing is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the hearing is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hearing is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the hearing is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hearing is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the hearing is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

A. siRNAs

[0024] In some embodiments, the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0025] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

[0026] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621. In SEQ ID NO: 3621, thymine (T) may be replaced with Uracil (U). In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.

[0027] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double -stranded RNA duplex. In some embodiments, the first base pair of the double -stranded RNA duplex is an AU base pair.

[0028] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0029] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0030] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human FGG mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human FGG mRNA.

[0031] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non -human primate FGG mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate FGG mRNA. [0032] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human FGG mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 40 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 20 human off- targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human FGG mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742. In any of SEQ ID NOs: 1-1742, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-

1742 is modified to an C.

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484. In any of SEQ ID NOs: 1743-3484, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743- 3484 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an C.

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748. In any of SEQ ID NOs: 3713-3748, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713- 3748 is modified to an C.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784. In any of SEQ ID NOs: 3749-3784, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749- 3784 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an C.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021. In any of SEQ ID NOs: 3879-3941 or 4020-4021, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023. In any of SEQ ID NOs: 3942-4002 or 4022-4023, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942- 4002 or 4022-4023 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in any of Tables 3-7. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-6 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U.

[0040] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 66B. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0041] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 79. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0042] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 83. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0043] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 87. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0044] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 93. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0045] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 97. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0046] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 101. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0047] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 105. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0048] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 109. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0049] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 113. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0050] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 117. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0051] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 121. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 121. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0052] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 125. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0053] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 166. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0054] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 170. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0055] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0056] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0057] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3 ’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0058] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0059] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G. The siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0060] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0061] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 352. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0062] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1003. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0063] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1011. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0064] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1278. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0065] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3785. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0066] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).

[0067] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2094. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0068] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2745. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0069] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2753. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0070] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0071] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3723, 3724, 3726, or 3747. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or 3747. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0072] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3723. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:

3723, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0073] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3724. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:

3724, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0074] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3726. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0075] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0076] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790 and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).

[0077] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3759. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0078] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3760. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0079] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3762. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0080] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3783. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0081] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

B. ASOs

[0082] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0083] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621. C. Modification patterns

[0084] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0085] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modified intemucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages, or a range of modified intemucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages. [0087] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'- deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2’-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises 2’-O-methoxyethyl. In some embodiments, the modified nucleoside comprises a methoxyethyl. For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O-methoxyethyl thymine. In some embodiments, the modified nucleoside comprises 2'-O-methyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N -methylacetamido (2'-0-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'- deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. . In some embodiments, the modified nucleoside comprises an acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0088] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:

[0089] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure: 3’ nucleotide

wherein the base can be any pyrimidine or purine.

[0090] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:

are independently an H or a 3 ’ or 5 ’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0091] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:

’ methylphosphonate 2’-0-methyl uridine).

[0092] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0093] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0094] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a moiety attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5 ’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0095] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2 ’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2 ’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0096] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0097] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I) or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0098] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’ deoxy nucleoside.

[0099] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2 ’-fluoromodified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[00100] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2 ’-fluoro; all pyrimidine nucleosides comprise 2 ’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2 ’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.

[00101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[00102] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[00103] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., a N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N- acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.

[00104] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting, neural (e.g., CNS (e.g., brain), or CSF targeting. . The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[00105] Non-limiting examples of GalNAc ligands are shown in FIG. 1 and FIG. 2. In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG. 1. In the GalNAc ligand shown in FIG. 1, J indicates a point of attachment to an oligonucleotide. In some embodiments, J is at a 5’ end of the oligonucleotide. In some embodiments, J is at a 3’ end of the oligonucleotide. In the GalNAc ligand shown in FIG. 1, n may be any number. For example, n may be 1-10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range defined by any two of the aforementioned integers. In some embodiments, n is 2. In embodiments in which n is 2 and the oligonucleotide is connected at J, the GalNAc moiety may be referred to as “GalNAc# 1” or “GalNAc 1.”

[00106] In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG. 2. The wavy line in FIG. 1 indicates a point of attachment to an oligonucleotide. In some embodiments, the wavy line is at a 5’ end of the oligonucleotide. In some embodiments, the wavy line is at a 3’ end of the oligonucleotide. In embodiments in which the oligonucleotide is connected at the wavy line, the GalNAc moiety may be referred to as “GalNAc#23” or “GalNAc23.”

[00107] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[00108] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’ -methyl modification may be included, and vice versa. [00109] In some embodiments, pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[00110] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[00111] In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines. [00112] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[00113] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[00114] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[00115] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2 ’-fluoromodified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro -modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[00116] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’- fluoro -modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines;

1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2 ’-fluoro -modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro -modified pyrimidines in a row.

[00117] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2 ’-fluoro -modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[00118] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2 ’-fluoro -modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[00119] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’-end group may be or include a 5 ’-end phosphorothioate, 5 ’-end phosphorodithioate, 5 ’-end vinylphosphonate (5’-VP), 5’-end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans-vinylphosphonate or cis-vinylphosphonate. The 5 ’-end group may include an extra 5’ phosphate. A combination of 5 ’-end groups may be used.

[00120] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used. [00121] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises atrans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.

5’ vinylphosphonate 2’-O-methyl uridine

[00122] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[00123] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.

1. Hydrophobic moieties

[00124] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[00125] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. [00126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[00127] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and/or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[00128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[00129] In some embodiments, the oligonucleotide comprises any aspect of the following structure:

. In some embodiments, the oligonucleotide comprises any aspect 5' oligonucleotide of the following structure:

. In some embodiments, the oligonucleotide comprises any aspect of the following structure:

some embodiments, the oligonucleotide comprises any aspect of the following structure:

some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether. [00130] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5 ’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue. Table 1: Hydrophobic moiety examples

[00131] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.

[00132] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[00133] The lipid moiety may comprise or consist of the following structure

some embodiments, the lipid moiety comprises or consists of the following structure:

some embodiments, the lipid moiety comprises the following structure:

some embodiments, the lipid moiety comprises or consist of the following structure:

In some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.

[00134] The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.

[00135] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[00136] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:

. n some embodiments, n is 1 -3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[00137] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol). [00138] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.

2. Sugar moieties

[00139] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N- acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[00140] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or tri valent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[00141] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[00142] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):

or a salt thereof, wherein

J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR⁶, or if z is 1, Y is C(R⁶)2;

Q is selected from:

C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO₂, -OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ - N(R⁷)C(O)N(R⁷)₂, -OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, -S(O)R⁷, and Ci ₆ alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;

R¹ is a linker selected from:

-O-, -S-, -N(R⁷)-, -C(O)-, -C(O)N(R⁷)-, -N(R⁷)C(O)-_ -N(R⁷)C(O)N(R⁷)-, -OC(O)N(R⁷)-, - N(R⁷)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)₂-, -OS(O)₂-, -OP(O)(OR⁷)O-, -SP(O)(OR⁷)O-, - OP(S)(OR⁷)O-, -OP(O)(SR⁷)O-, -OP(O)(OR⁷)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, - OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR⁷)NR⁷-, -OP(O)(N(R⁷)₂)NR⁷-, -OP(OR⁷)O-, - OP(N(R⁷)₂)O-, -OP(OR⁷)N(R⁷)-, and -OPN(R⁷)₂NR⁷-; each R² is independently selected from:

C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ -N(R⁷)C(O)N(R⁷)₂, - OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, and -S(O)R⁷;

R³ and R⁴ are each independently selected from:

-OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ -N(R⁷)C(O)N(R⁷)₂, - OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, and -S(O)R⁷; each R⁵ is independently selected from: -OC(O)R⁷, -OC(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ -N(R⁷)C(O)N(R⁷)₂, - N(R⁷)C(O)OR⁷, -C(O)R⁷, -C(O)OR⁷, and -C(O)N(R⁷)₂; each R⁶ is independently selected from: hydrogen; halogen, -CN, -NO₂, -OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ - N(R⁷)C(O)N(R⁷)₂, -OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, and -S(O)R⁷; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO₂, -OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ - N(R⁷)C(O)N(R⁷)₂, -OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, and -S(O)R⁷; each R⁷ is independently selected from: hydrogen;

Ci-6 alkyl, C₂-6 alkenyl, and C₂.e alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, -NH₂, =0, =S, - O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(Ci-e alkyl)₂, -NH(Ci-e alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; and

C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - N0₂, -NH₂, =0, =S, -O-C1-6 alkyl, -S-Ci-e alkyl, -N(Ci-e alkyl)₂, -NH(Ci-e alkyl), C1-6 alkyl, C₂.e alkenyl, C₂.„ alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and Ci-ehaloalkyl.

[00143] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO₂, -OR⁷, -SR⁷, -N(R⁷)₂, -C(O)R⁷, -C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ - N(R⁷)C(O)N(R⁷)₂, -OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, and -S(O)R⁷. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, and -NH₂. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, and -NH₂. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R¹ is selected from -OP(O)(OR⁷)O-, -SP(O)(OR⁷)O-, -OP(S)(OR⁷)O-, -OP(O)(SR⁷)O-, - OP(O)(OR⁷)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, - OP(O)(OR⁷)NR⁷-, -OP(O)(N(R⁷)₂)NR⁷-, -OP(OR⁷)O-, -OP(N(R⁷)₂)O-, -OP(OR⁷)N(R⁷)-, and -OPN(R⁷)₂. NR⁷. In some embodiments, R¹ is selected from -OP(O)(OR⁷)O-, -SP(O)(OR⁷)O-, -OP(S)(OR⁷)O-, - OP(O)(SR⁷)O-, -OP(O)(OR⁷)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, and -OP(OR⁷)O-. In some embodiments, R¹ is selected from -OP(O)(OR⁷)O-, -OP(S)(OR⁷)O-, - OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, and -OP(OR⁷)O-. In some embodiments, R¹ is selected from - OP(O)(OR⁷)O- and -OP(OR⁷)O-. In some embodiments, R² is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR⁷, -OC(O)R⁷, -SR⁷, -N(R⁷)2, -C(O)R⁷, and -S(O)R⁷. In some embodiments, R² is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR⁷, -OC(O)R⁷, -SR⁷, and -N(R⁷)2. In some embodiments, R² is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR⁷ and - OC(O)R⁷. In some embodiments, R³ is selected from halogen, -OR⁷, -SR⁷, -N(R⁷)2, -C(O)R⁷, -OC(O)R⁷, and -S(O)R⁷ In some embodiments, R³ is selected from -OR⁷ -SR⁷, -OC(O)R⁷, and -N(R⁷)2. In some embodiments, R³ is selected from -OR⁷ - and -OC(O)R⁷. In some embodiments, R⁴ is selected from halogen, -OR⁷, -SR⁷, -N(R⁷)2, -C(O)R⁷, -OC(O)R⁷, and -S(O)R⁷ In some embodiments, R⁴ is selected from -OR⁷ -SR⁷, -OC(O)R⁷, and -N(R⁷)2 In some embodiments, R⁴ is selected from -OR⁷ - and -OC(O)R⁷. In some embodiments, R⁵ is selected from -OC(O)R⁷, -OC(O)N(R⁷)2, -N(R⁷)C(O)R⁷ -N(R⁷)C(O)N(R⁷)2, and -N(R⁷)C(O)OR⁷. In some embodiments, R⁵ is selected from -OC(O)R⁷ and -N(R⁷)C(O)R⁷. In some embodiments, each R⁷ is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O- C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R⁷ is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, - NH2, =0, =S, -O-C1.6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, and -NH(CI-6 alkyl). In some embodiments, each R⁷ is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl; R¹ is selected from -OP(O)(OR⁷)O-, -OP(S)(OR⁷)O-, -0P(0)(0 )0-, -OP(S)(O )0-, -OP(O)(S )0-, and - OP(OR⁷)O-; R² is Ci alkyl substituted with -OH or -0C(0)CH3;

R³ is -OH or -0C(0)C some embodiments, the compound comprises:

[00144] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified intemucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[00145] Some embodiments include the following, where J is the oligonucleotide:

include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[00146] Some embodiments include the following, where J is the oligonucleotide:

J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. [00147] Some embodiments include the following, where J is the oligonucleotide:

include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[00148] Some embodiments include the following, where J is the oligonucleotide:

The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[00149] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[00150] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[00151] Some embodiments include the following, where J is the oligonucleotide:

include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide.

J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[00152] Some embodiments include the following, where J is the oligonucleotide:

The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[00153] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):

Formula IV, or

Formula V, or a salt thereof, wherein

J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1 ; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;

Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR⁷, -SR⁷, -N(R⁷)2, -C(O)R⁷, - C(O)N(R⁷)₂, -N(R⁷)C(O)R⁷ -N(R⁷)C(O)N(R⁷)₂, -OC(O)N(R⁷)₂, -N(R⁷)C(O)OR⁷, -C(O)OR⁷, -OC(O)R⁷, - S(O)R⁷, and Ci-e alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;

R¹ is a linker selected from: -O-, -S-, -N(R⁷)-, -C(O)-, -C(O)N(R⁷)-, -N(R⁷)C(O)-_ -N(R⁷)C(O)N(R⁷)-, -OC(O)N(R⁷)-, -N(R⁷)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)₂-, -OS(O)₂-, -OP(O)(OR⁷)O-, - SP(O)(OR⁷)O-, -OP(S)(OR⁷)O-, -OP(O)(SR⁷)O-, -OP(O)(OR⁷)S-, -OP(O)(O )O-, -SP(O)(O )O-, - OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR⁷)NR⁷-, -OP(O)(N(R⁷)₂)NR⁷-, -OP(OR⁷)O-, - OP(N(R⁷)₂)O-, -OP(OR⁷)N(R⁷)-, and -OPN(R⁷)₂NR⁷-; each R⁷ is independently selected from: hydrogen, Ci-6 alkyl, C2-6 alkenyl, and C2-ealkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, -SH, -NO₂, -NH₂, =0, =S, -O-C1.6 alkyl, -S-C1.6 alkyl, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, -NH₂, =0, =S, -O-Ci.₆ alkyl, -S-C1.6 alkyl, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkyl), C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[00154] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[00155] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00156] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[00157] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00158] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[00159] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00160] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[00161] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00162] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[00163] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00164] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00165] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:

. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00166] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

. The structure in this compound atached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00167] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[00168] The structures in these compounds in some instances are attached to the oligonucleotide (J or

K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 ’ or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00169] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[00170] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[00171] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[00172] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking to the oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide. [00173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[00174] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

3. siRNA modification patterns

[00175] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5’-NfsnsNfiiNfiiNfNfNfhNfiiNfnNfiiNfiiNfsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5 ’ -nsnsnnNfiiNfNfNfnnnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfhNfiiNfimnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfhNfiiNfNfNfiiNfiiNfnNfiiNfiiNfsnsnN-moiety-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfiiNfNfNfnnnnnnnnnnsnsnN-moiety-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a sugar moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfiiNfiiNfnNfnNfhNfiiNfnNfiiNfsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern IOS: 5'- nsnsnnNfNfiiNfNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 1 IS: 5'-nsnsnnNfnnnNfnnnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 12S: 5'-snnnnNfNfnNfNfnnnnNfimNfimsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 13S: 5'- snnnnNfNfnNfdNnNfNfimNfimnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 14S: 5'-snnNfNfimnnNfimnnNfiiNfNfnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 15S: 5'-snnNfiiNfnNfNfdNnNfNfnnNfnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 16S: 5'- snnnnNfnNfNfNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 17S: 5'-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 18S: 5'-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 19S: 5'-snnnnNfnnnNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 20S: 5'-snnnnnNfNfNfNfnNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2 IS: 5'- snnnnnnNfNfNfNfNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22S: 5'-snnnnNfNfhNfNfnNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23S: 5'-snnnnNfhNfNfdTnnnnnnnnnnsnsn-3', wherein “dT” is deoxythymidine, “Nf ’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24S: 5'- snnnnNfNfnnNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25S: 5'-snnnnnNfNfhNfimnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26S: 5'-snnnnnnNfhNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27S: 5'-snnnnnnnNfNfnNfimnnnnnnsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28S: 5'-snnnnnnnnNfiiNfnNfhnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29S: 5'-snnnnnnnNfNfNfNfnnnnnnnnsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30S: 5'-snnnnmnNfNfNfNfimnnmnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3 IS: 5'-snnnnmnNfNfNfNfimnmnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32S: 5'-snnnnmnNfNfNfNfhtmnnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33S: 5'-snnnnnmNfNfNfNfimnmnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34S: 5'-snnnnmnNfNfNfNfimnnnnmnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35S: 5'-snnnnmnNfNfNfNfimnnnmnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36S: 5'-snnnnmnNfNfNfNfimnntmnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnmnNfNfNfNfimnnmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38S: 5'- snnnnmNfiiNfNfNfNfimnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39S: 5'-snnnnmnNfNfNfNfimmnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40S: 5'-snnnnNfhNfNfNfdnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 4 IS: 5'- snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 42S: 5'-snnnnnNfnnNfhNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnNfimNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 44S: 5'- snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 45S: 5'-snnnnNfnnNfNfiiNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnmNfhNfNfNfNfnntmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 47S: 5'- snnnnmnNfNfNfNfnnntmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 48S: 5'-snnnnmnNfNfNfNfimtmnnnnnnnsnsn-3’, wherein “Nf” is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 49S: 5'-snnnnNfNfnnNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 50S: 5'-snnnnnnNfNfNfNfnnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 5 IS: 5'-snnnnNfiiNfiiNfhnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 52S: 5'- snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 53S: 5'-snnnnnnNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 54S: 5'-snnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 55S: 5'- snnnnNfnnNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 56S: 5'-snnnnNfNfNfNfNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 57S: 5'-snnnnNfimNfNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 58S: 5'- snnnnNfnNfNfNfdNnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 59S: 5'-snnnnNfnNfNfNfdTnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 60S: 5'-snnnnNfhNfiiNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 6 IS: 5'-snnnnNfimNfNfimnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification patem 62S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 63S: 5'-snnnnnnNfNfNfNfimnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 64S: 5'-snnnnNfhNfiiNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 65S: 5'- snnnnmNfiiNfNfNfNfimnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 66S: 5'-snnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.

[00176] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’-nsNfsnNfiiNfiiNfiiNfnnnNfnNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfiiNfNfimnnNfhNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnNfiiNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’-nsNfsnNfiiNfnnnnnnnNfiiNfimnsnsn-3’, wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 5 AS: 5’-nsNfsnnnnnnnnnnnNfhNfiinnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfimnnNfnNfimnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’-nsNfsnNfiiNfnNfiiNfiiNfnNfhNfnNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 8 AS: 5’-nsNfsnnnnnnnnnnnNfimnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nNfiiNfiiNfnNfiiNfhNfiiNfiiNfnNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 10AS: 5'-nsNfsnNfimnNfhNfiiNfiiNfnNfiiNfnsnsn-3', wherein “Nf ’ is a 2 ’-fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 1 IAS: 5'- nsNfsnNfnnNfnnNfnNfiiNfiiNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsndTndNnNfhNfhdNnNfndNnNfhsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern HAS: 5'-nsNfsndTndNnNfnNfndNndTndNndTnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnnNfnnnNfiiNfiiNfiiNfiiNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-dTsNfsnnnNfiiNfiiNfnNfnNfnNfhNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 16As: 5'-NfsNfsnnnNfiiNfhNfiiNfiiNfnNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'- nsNfsnnnNfiiNfnNfnNfiiNfiiNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnNfimnNfiiNfhNfiiNfnNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'-nsNfsnNfimNfNfiiNfnNfnNfiiNfnNfnsnsn-3', wherein “Nf ’ is a 2 ’-fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'- nsNfsnNfnnNfnnnnNfnNfiiNfnNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnNfiiNfnnnNfnNfiiNfiiNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22AS: 5'-nsNfsnNfimNfnnNfnNfnNfimnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23AS: 5'- nsNfsnnnNfiiNfnNfnNfiiNfiiNfimnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24AS: 5'-nsNfsnnnNfhNfhNfnNfiiNfimnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25 AS: 5'-nsNfsnnNfhNfimNfiiNfnNfiiNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26AS: 5'- nsNfsnnNfnNfNfimnNfiiNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-nsNfsnNfhNfnNfnNfiiNfiiNfiiNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28AS: 5'-nsNfsnnnNfNfimNfnNfnNfhNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29AS: 5'- nsNfsnnnNfNfnnnnNfnNfiiNfnNfiisnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnNfiiNfNfnNfhNfiiNfiiNfnNfnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3 IAS: 5'-nsNfsnnNfiiNfimNfimnNfnNfnNfhsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32AS: 5'- nsNfsnnNfnNfNfiiNfimnNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnnnNfimnnNfhNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34AS: 5'-nsNfsnnNfhNfiiNfnnNfnNfiiNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35AS: 5'- nsNfsnNfnnNfnnnnNfnNfiiNfnNfsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36AS: 5'-nsNfsnNfimNfnnnnNfnNfhNfnsNfsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37AS: 5'-nsNfsnNfimNfnnnnNfiiNfnNfiisnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38AS: 5'- nsNfsnNfimNfimnnNfiiNfirNfsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-nsNfsnNfimNfnnNfnNfhNfnNfiiNfsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40AS: 5'-nsNfsnNfimNfnnNfnNfnNfiiNfhsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 41AS: 5'- nsNfsnNfnnnfimNfnnfnNfiiNfsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.

[00177] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 1 IS and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 23 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 25 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 3 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 41S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 43 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, 1 IAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 48S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 5 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 55S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 65 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 66S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.

[00178] In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,

IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,

30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,

50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, HS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S,

44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S,

64S, 65S, or 66S and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S,

40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S,

60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,

34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S,

54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,

50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S,

44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S,

64S, 65S, or 66S and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S,

60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 1 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51 S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,

38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,

58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 14AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,

50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S,

47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 17AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 18AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 19AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 20AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 2 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 22AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 23AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 24AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 25AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 26AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 28AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 29AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 30AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 3 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 32AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 33AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 34AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 35AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 36AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 37AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,

62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,

18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 39AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,

54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 40AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S,

9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 4 IAS.

[00179] In some embodiments, the sense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 2 IAS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the antisense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S . In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO 1 .

[00180] In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines.

[00181] In some embodiments, pyrimidines of the sense strand comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O- methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[00182] In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise 2’ -fluoro modified purines.

[00183] In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’ -fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O- methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2’-fluoro modified purines.

[00184] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2 ’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines.

[00185] In some embodiments, pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[00186] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O- methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines. [00187] In some embodiments, all purines of the antisense strand comprise 2’ -fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise 2 ’-fluoro modified purines.

[00188] Disclosed herein, in some embodiments, are modified oligonucleotides. The modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency. The siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject. The modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.

[00189] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs. In some embodiments, the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand. One strand (antisense strand) is complementary to a FGG mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a FGG mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the FGG mRNA. In some embodiments, there are 1-2 phosphorothioates at the 3’ end. In some embodiments, there are 1 or no phosphorothioates at the 5’ end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached at the 5’ end via a phosphodiester bond.

[00190] In some cases, the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern. In some embodiments of the modification pattern, position 9 counting from the 5’ end of the sense strand may have a 2’F modification. In some embodiments, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2’0Me modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

[00191] In some embodiments, when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules. [00192] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

[00193] In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

[00194] Disclosed herein, in some embodiments are compositions comprising an oligonucleotide that targets FGG and when administered to a cell decreases expression of FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the antisense strand sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified. Some embodiments relate to methods that include administering the composition to a subject.

[00195] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’ -fluoro modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’ -fluoro modified purines. In some embodiments, the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;

(e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’- O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; and wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines.

[00196] In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified.

[00197] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in any of 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in any of Tables 88A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00198] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 8A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 8A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 8A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00199] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 8B. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 8B. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 8B. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00200] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 18A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 18A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 18A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 18A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 18A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 18A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00201] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 22A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 22A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 22A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00202] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 26A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 26A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 26A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00203] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 31A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31 A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31 A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 31A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 31A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00204] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 33A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 33A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 33A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00205] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 37A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 37A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 37A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00206] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 42A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 42A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 42A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00207] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 47A. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 47A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 47A. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00208] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 66B. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 66B. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 66B. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00209] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 78. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 78. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 78. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00210] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 82. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 82 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 82 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 82. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 82. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 82. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00211] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 86. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 86. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 86. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00212] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 92. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 92. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 92. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00213] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 96. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 96. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 96. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00214] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 100. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 100. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 100. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00215] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 104. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 104. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 104. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00216] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 108. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 108. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 108. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00217] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 112. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 112. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 112. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00218] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 116. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 116. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 116. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00219] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 120. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 120. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 120. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00220] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 124. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 124. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 124. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00221] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 165. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 165 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 165 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 165. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 165. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 165. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00222] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 169. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 169 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 169 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 169. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 169. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 169. The siRNA may include some unmodified intemucleoside linkages or nucleosides. In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 175. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 175. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 175. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[00223] In some embodiments, the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 176. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in

-I l l- Table 176 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 176 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 176. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 176. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 176. The siRNA may include some unmodified intemucleoside linkages or nucleosides. [00224] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3591-3594. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOS: 3591-3594. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00225] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3591. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO:

3591. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00226] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3592. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:

3592, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3592. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17). [00227] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3593. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO:

3593. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00228] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3594. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:

3594, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00229] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3641-3676. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3641-3676. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00230] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3651. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3651. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17). [00231] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3652. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3652. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00232] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3654. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00233] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3675. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3675. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00234] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3795-3802. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3795-3802. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17). [00235] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3795. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3795. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).

[00236] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3595-3598. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOS: 3595-3598. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00237] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3595. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3595. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00238] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3596. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3596. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety. [00239] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3597. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3597. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00240] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3598. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3598. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00241] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3677-3712. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3677-3712. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00242] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3687. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3687. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety. [00243] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3688. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3688. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00244] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00245] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3747. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00246] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3803-3808. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3803-3808. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety. [00247] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00248] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3813-3843. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3813-3843. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include a GalNAc moiety.

[00249] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 4018-4019. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 4018-4019. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include a GalNAc moiety.

[00250] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3844-3878. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3844-3878. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

[00251] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 4003-4017. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017. The antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 4003-4017. The antisense strand may include some unmodified intemucleoside linkages or nucleosides. The antisense strand may include a GalNAc moiety.

4. ASO modification patterns

[00252] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern ASO 1 : 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3’ (SEQ ID NO: 3640), wherein “dN” is any deoxynucleotide, “n” is a 2’-O-methyl or 2 ’-O-methoxyethyl -modified nucleoside, and “s” is a phosphorothioate linkage. In some embodiments, the ASO comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.

D. Formulations

[00253] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[00254] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. II. METHODS AND USES

[00255] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

[00256] Some embodiments relate to a method of treating a disease or disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[00257] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder (e.g., hearing disorder) in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

[00258] Some embodiments relate to a method of preventing a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[00259] Some embodiments relate to a method of inhibiting a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[00260] Some embodiments relate to a method of reversing a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[00261] In some embodiments, the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection.

A. Disorders

[00262] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. A disorder can include a disease. In some embodiments, the disorder is a hearing disorder. Non-limiting examples of hearing disorders include idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, and conductive hearing loss. The disorder may include hearing loss. The disorder may include sensorineural hearing loss. The disorder may include sudden hearing loss. The disorder may include ISSNHL. The disorder may include noise-induced hearing loss. The disorder may include noise-induced sensorineural hearing loss. The disorder may include tinnitus. The disorder may include conductive hearing loss.

[00263] In some cases, the disorder may be diagnosed with the use of a questionnaire or a scoring system. In some cases, the disorder is diagnosed according to a clinical hearing loss criteria. In some cases, the disorder is diagnosed by a healthcare professional (e.g., physician or the like).

[00264] In some embodiments, the disorder comprises one or more disorders (e.g., any of the disorders disclosed herein). In some embodiments, the disorder comprises two disorders. In some embodiments, the disorder comprises three disorders. In some embodiments, the disorder comprises four disorders. In some embodiments, the disorder comprises five disorders.

B. Subjects

[00265] Some embodiments of the methods described herein include treatment of a subject. Nonlimiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human.

[00266] In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is 45 years old or greater. In some embodiments, the subject is 50 years old or greater. In some embodiments, the subject is 55 years old or greater. In some embodiments, the subject is 60 years old or greater. In some embodiments, the subject is 65 years old or greater. In some embodiments, the subject is 70 years old or greater. In some embodiments, the subject is 75 years old or greater. In some embodiments, the subject is 80 years old or greater. In some embodiments, the subject is 85 years old or greater.

[00267] In some embodiments, the subject has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or more. In some embodiments, the subject has a BMI of 25- 29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or more. In some embodiments, the subject has a BMI of 30-39. In some embodiments, the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 25-50. [00268] In some embodiments, the subject has a personal history with the disorder. In some embodiments, the subject has a familial history with the disorder. In some embodiments, the subject is at high risk of contracting the disorder.

[00269] In some embodiments, the subject has a hearing disorder. In some embodiments, the subject has idiopathic sudden sensorineural hearing loss (ISSNHL). In some embodiments, the subject has noise- induced sensorineural hearing loss. In some embodiments, the subject has hearing loss. The subject may have hyperfibrinogenemia. The hearing loss may result from hyperfibrinogenemia. In some embodiments, the subject has sensorineural hearing loss. In some embodiments, the subject has tinnitus. In some embodiments, the subject has conductive hearing loss. The subject may be deaf. The subject may be dumb.

C. Baseline measurements

[00270] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. In some embodiments, the baseline measurement is a hearing disorder baseline measurement. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. Non-limiting examples of baseline measurements include a baseline measurement of pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions. The baseline measurement may include a baseline fibrinogen measurement, a baseline FGG mRNA measurement, or a baseline FGG protein measurement.

[00271] In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation of the subject. In some embodiments, the baseline measurement is obtained by questioning the subject. In some embodiments, the baseline measurement is obtained by the subject filling out a questionnaire.

[00272] In some embodiments, the baseline measurement is a baseline audiometry measurement. In some embodiments, the baseline measurement is a baseline pure-tone audiometry measurement. In some embodiments, the baseline pure-tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, or 8000 Hz. In some embodiments, the baseline-pure tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz. In some embodiments, the baseline measurement is a baseline pure tone threshold measurement.

[00273] In some embodiments, the baseline measurement is a baseline speech audiometry and speech reception threshold measurement. In some embodiments, the baseline speech audiometry and speech reception threshold measurement is a baseline speech recognition threshold. In some embodiments, the baseline speech audiometry and speech reception threshold measurement is a baseline spondee threshold. In some embodiments, the baseline speech audiometry and speech reception threshold measurement is a baseline speech detection threshold. In some embodiments, the baseline speech audiometry and speech reception threshold measurement is a baseline speech awareness threshold. In some embodiments, the baseline measurement is a baseline German speech intelligibility test (Freiburger Sprachtest) measurement.

[00274] In some embodiments, the baseline measurement is a baseline tympanometry measurement. In some embodiments, the baseline tympanometry measurement is measured using a tympanometer. In some embodiments, the baseline measurement is a baseline stapedius reflex measurement. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 or 4000 Hz, or a combination thereof, are measured. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli at intensities including or between 70 to 115 dB of sound pressure are measured. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 and 4000 Hz at intensities of 70 to 115 dB of sound pressure are measured.

[00275] In some embodiments, the baseline measurement is a baseline brainstem audiometry measurement. In some embodiments, the baseline measurement is an absolute wave latency. In some embodiments, the baseline measurement is a baseline wave amplitude. In some embodiments, the baseline measurement is a baseline interwave interval between waves.

[00276] In some embodiments, the baseline measurement is a baseline otoacoustic emission measurement.

[00277] In some embodiments, the baseline measurement is a baseline level of fibrinogen. In some embodiments, the baseline measurement is a baseline level of circulating fibrinogen.

[00278] In some cases, the disorder (e.g., baseline measurement) may be diagnosed or measured with the use of a questionnaire or a scoring system. In some cases, the disorder is diagnosed according to a clinical hearing loss criteria. In some cases, the disorder is diagnosed by a healthcare professional (e.g., physician or the like).

[00279] Baseline measurements may include a baseline FGG protein measurement, or a baseline FGG mRNA measurement.

[00280] Baseline measurements may include any one or more of the baseline measurements disclosed herein.

[00281] In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained invasively using an imaging device.

[00282] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.

[00283] In some embodiments, the baseline measurement is a baseline FGG protein measurement. In some embodiments, the baseline FGG protein measurement comprises a baseline FGG protein level. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample weight. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample volume. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per total protein within the sample. In some embodiments, the baseline FGG protein measurement is a baseline tissue FGG protein measurement. In some embodiments, the baseline FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline FGG protein level is measured in the whole body. In some embodiments, the baseline FGG protein level is measured in the brain. In some embodiments, the baseline FGG protein level is measured in the liver. In some embodiments, the baseline FGG protein level is measured in the blood.

[00284] In some embodiments, the baseline measurement is a baseline FGG mRNA measurement. In some embodiments, the baseline FGG mRNA measurement comprises a baseline FGG mRNA level. In some embodiments, the baseline FGG mRNA level is measured in the liver. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample weight. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample volume. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total mRNA within the sample. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total nucleic acids within the sample. In some embodiments, the baseline FGG mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline FGG mRNA measurement is a baseline tissue FGG mRNA measurement. In some embodiments, the baseline FGG mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the FGG mRNA.

[00285] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject. In some embodiments, the sample is obtained from the subject in a fasted state. In some embodiments, the sample is obtained from the subject after an overnight fasting period. In some embodiments, the sample is obtained from the subject in a fed state.

[00286] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. A blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. A blood sample may be a serum sample. In some embodiments, the sample is a CSF sample. In some embodiments, the sample includes a CSF sample. In some embodiments, the sample is a CNS sample. In some embodiments, the sample includes a CNS sample. In some embodiments, the sample includes a sinus fluid sample. In some embodiments, the sample includes an aural fluid sample.

[00287] In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises liver or brain tissue. For example, the baseline FGG mRNA measurement, or the baseline FGG protein measurement, may be obtained in a brain or liver sample obtained from the patient. In some embodiments, the tissue comprises neural tissue. In some embodiments, the tissue comprises neuronal tissue. In some embodiments, the tissue comprises neurons. In some embodiments, the tissue comprises glial cells. In some embodiments, the tissue comprises epithelial cells. In some embodiments, the tissue comprises liver tissue. The liver may include hepatocytes. In some embodiments, the tissue comprises brain tissue. In some embodiments, the tissue comprises ear tissue. In some embodiments, the tissue comprises auditory tissue. In some embodiments, the tissue comprises cochlea. In some embodiments, the tissue comprises a nerve. In some embodiments, the tissue comprises an auditory nerve. In some embodiments, the tissue comprises brainstem.

[00288] In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a liver cell (e.g., hepatocyte), or a brain cell. In some embodiments, the cell is a liver cell. In some embodiments, the liver cell is a hepatocyte. In some embodiments, the cell is a brain cell. In some embodiments, the cell is a neuron. In some embodiments, the cell is an nerve cell. In some embodiments, the cell is a glial cell. In some embodiments, the cell is an epithelial cell. In some embodiments, the cell is a vasculature cell. In some embodiments, the cell is an auditory cell.

D. Effects

[00289] Some embodiments of the methods described herein include obtaining a measurement from a subject. In some embodiments, the measurement is a hearing disorder measurement. For example, in some embodiments, a measurement is obtained from the subject prior to treating the subject. Non-limiting examples of measurements include a measurement of pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions. The measurement may include a fibrinogen measurement, a FGG mRNA measurement, or a FGG protein measurement.

[00290] In some embodiments, the measurement indicates that the disorder has been treated. In some embodiments, the measurement indicates that the severity of the disorder has decreased. In some embodiments, the measurement indicates that the severity of a sign or symptom of the disorder has decreased. In some embodiments, the measurement indicates that the frequency of a sign or symptom of the disorder has decreased.

[00291] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated.

[00292] In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a third sample, a fourth sample, or a fifth sample.

[00293] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.

[00294] In some embodiments, the composition reduces the measurement relative to the baseline measurement. For example, an adverse phenotype of a hearing disorder may be reduced upon administration of the composition. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00295] In some embodiments, the composition increases the measurement relative to the baseline measurement. For example, a protective hearing phenotype may be increased upon administration of the composition. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00296] In some embodiments, the measurement is an audiometry measurement. In some embodiments, the measurement is a pure-tone audiometry measurement. In some embodiments, the pure- tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, or 8000 Hz. In some embodiments, the baseline-pure tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz. In some embodiments, the measurement is a pure tone threshold measurement. In some embodiments, the audiometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the audiometry measurement is improved by about 10% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 10%, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00297] In some embodiments, the measurement is a speech audiometry and speech reception threshold measurement. In some embodiments, the speech audiometry and speech reception threshold measurement is a speech recognition threshold. In some embodiments, the speech audiometry and speech reception threshold measurement is a spondee threshold. In some embodiments, the speech audiometry and speech reception threshold measurement is a speech detection threshold. In some embodiments, the speech audiometry and speech reception threshold measurement is a speech awareness threshold. In some embodiments, the measurement is a German speech intelligibility test (Freiburger Sprachtest) measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 10% or more, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 10%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00298] In some embodiments, the measurement is a tympanometry measurement. In some embodiments, the tympanometry measurement is measured using a tympanometer. In some embodiments, the measurement is a stapedius reflex measurement. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 and 4000 Hz at intensities of 70 to 115 dB of sound pressure are measured. In some embodiments, the tympanometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the tympanometry measurement is improved by about 10% or more, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 10%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00299] In some embodiments, the measurement is a brainstem audiometry measurement. In some embodiments, the measurement is an absolute wave latency. In some embodiments, the measurement is a wave amplitude. In some embodiments, the measurement is a interwave interval between waves. In some embodiments, the brain stem audiometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the brain stem audiometry measurement is improved by about 10% or more, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 10%, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages. [00300] In some embodiments, the measurement is a otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the otoacoustic emission measurement is improved by about 10% or more, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 10%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00301] In some embodiments, the measurement is a fibrinogen measurement. In some embodiments, the measurement is a measurement of circulating fibrinogen. In some embodiments, the composition reduces the fibrinogen measurement relative to the baseline fibrinogen measurement. In some embodiments, the composition reduces the circulating fibrinogen measurement relative to the baseline circulating fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 10% or more, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 10%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00302] In some embodiments, the measurement is an FGG protein measurement. In some embodiments, the FGG protein measurement comprises an FGG protein level. In some embodiments, the FGG protein level is a FGG protein level in the whole body. In some embodiments, the FGG protein level is a FGG protein level in the blood. In some embodiments, the FGG protein level is a FGG protein level in the brain. In some embodiments, the FGG protein level is a FGG protein level in the liver. In some embodiments, the FGG protein level is indicated as a mass or percentage of FGG protein per sample weight. In some embodiments, the FGG protein level is indicated as a mass or percentage of FGG protein per sample volume. In some embodiments, the FGG protein level is indicated as a mass or percentage of FGG protein per total protein within the sample. In some embodiments, the FGG protein measurement is a circulating FGG protein measurement. In some embodiments, the FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

[00303] In some embodiments, the composition reduces the FGG protein measurement relative to the baseline FGG protein measurement. In some embodiments, the composition reduces circulating FGG protein levels relative to the baseline FGG protein measurement. In some embodiments, the composition reduces tissue (e.g., brain, liver, blood, or whole body) FGG protein levels relative to the baseline FGG protein measurement. In some embodiments, the reduced FGG protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the FGG protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by about 10% or more, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by no more than about 10%, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00304] In some embodiments, the measurement is an FGG mRNA measurement. In some embodiments, the FGG mRNA measurement comprises an FGG mRNA level. In some embodiments, the FGG mRNA level is measured in the liver. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample weight. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample volume. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total mRNA within the sample. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total nucleic acids within the sample. In some embodiments, the FGG mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the FGG mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of the FGG mRNA.

[00305] In some embodiments, the composition reduces the FGG mRNA measurement relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces FGG mRNA levels relative to the baseline FGG mRNA levels. In some embodiments, the reduced FGG mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a liver sample. In some embodiments, the FGG mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline v mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by about 10% or more, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by no more than about 10%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages.

III. DEFINITIONS

[00306] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[00307] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[00308] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[00309] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute.

“Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[00310] The terms “subject,” and “patient” may be used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[00311] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[00312] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[00313] The term “C_x.y” or “C_x-C_y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

[00314] The terms “C_x.yalkenyl” and “C_x.yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[00315] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane. A bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo [l.l.l]pentanyl.

[00316] The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Htickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[00317] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo [l. l.l]pentanyl, and the like. [00318] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and

5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. [00319] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[00320] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1- chloromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

[00321] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12- membered spiro bicycles, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems,

6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.

[00322] The term "heteroaryl" refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Htickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo [d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7- dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6 dihydrobenzo[h]quinazolinyl, 5,6 dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a- octahydrobenzo[h]quinazolinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2- d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5, 6,7,8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3- d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl).

[00323] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo- thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[00324] The term "heterocycloalkenyl" refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.

Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[00325] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non -aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[00326] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N- OH), hydrazino (=N-NH₂), -R^b0R^a, -R^bOC(O)R^a, -R^bOC(O)OR^a, -R^bOC(O)N(R^a)₂, -R^bN(R^a)₂, - R^bC(O)R^a, -R^bC(O)OR^a, -R^bC(O)N(R^a)₂, -R^bOR^cC(O)N(R^a)₂, -R^bN(R^a)C(O)OR^a, -R^bN(R^a)C(O)R^a, - R^bN(R^a)S(O)_tR^a (where t is 1 or 2), -R^bS(O)_tR^a (where t is 1 or 2), -R^bS(O)_tOR^a (where t is 1 or 2), and - R^bS(O)_tN(R^a)₂ (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO₂), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH₂), -R^b0R^a, -R^bOC(O)R^a, -R^bOC(O)OR^a, -R^b0C(0)N(R^a)₂, -R^bN(R^a)₂, -R^bC(O)R^a, -R^bC(O)OR^a, - R^bC(0)N(R^a)₂, -R^b0R^cC(0)N(R^a)₂, -R^bN(R^a)C(0)0R^a, -R^bN(R^a)C(0)R^a, -R^bN(R^a)S(O)_tR^a (where t is 1 or 2), -R^bS(O)_tR^a (where t is 1 or 2), -R^bS(O)_tOR^a (where t is 1 or 2) and -R^bS(O)_tN(R^a)₂ (where t is 1 or 2); wherein each R^a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R^a, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO₂), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH₂), -R^b0R^a, -R^b0C(0)R^a, -R^b0C(0)0R^a, -R^b0C(0)N(R^a)₂, -R^bN(R^a)₂, -R^bC(0)R^a, -R^bC(0)0R^a, - R^bC(0)N(R^a)₂, -R^b0R^cC(0)N(R^a)₂, -R^bN(R^a)C(0)0R^a, -R^bN(R^a)C(0)R^a, -R^bN(R^a)S(0)_tR^a (where t is 1 or 2), -R^bS(O)_tR^a (where t is 1 or 2), -R^bS(O)_tOR^a (where t is 1 or 2) and -R^bS(O)_tN(R^a)₂ (where t is 1 or 2); and wherein each R^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R^c is a straight or branched alkylene, alkenylene or alkynylene chain. [00327] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)” Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”.

[00328] In some embodiments, a "derivative" polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment. A derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.

[00329] Some embodiments refer to nucleic acid sequence information. It is contemplated that in some embodiments, thymine (T) may be interchanged with uracil (U), or vice versa. For example, some sequences in the sequence listing may recite Ts, but these may be replaced with Us in some embodiments. In some oligonucleotides with nucleic acid sequences that include uracil, the uracil may be replaced with thymine. Similarly, in some oligonucleotides with nucleic acid sequences that include thymine, the thymine may be replaced with uracil. In some embodiments, an oligonucleotide such as an siRNA comprises or consists of RNA. In some embodiments, the oligonucleotide may include of DNA. For example, the oligonucleotide may include 2’ deoxyribonucleotides. An ASO may comprise or consist of DNA. To any extent that the sequence listing contradicts the disclosure in the specification, the specification takes precedent. Some aspects include sequences with nucleotide modifications or modified intemucleoside linkages. Generally, and unless otherwise specified, Nf (e.g., Af, Cf, Gf, Tf, or Uf) refers to a 2’-fluoro-modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) refers to a 2’ deoxy nucleoside, n (e.g., a, c, g, t, or u) refers to a 2’-O-methyl modified nucleoside, and “s” refers to a phosphorothioate linkage.

[00330] A pyrimidine may include cytosine (C), thymine (T), or uracil (U). A pyrimidine may include C or U. A pyrimidine may include C or T. Where a pyrimidine is referred to, it may indicate a nucleoside or nucleotide comprising a pyrimidine. A purine may include guanine (G), inosine (I), adenine (A). Where a purine is referred to, it may indicate a nucleoside or nucleotide comprising a purine.

[00331] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

VI. EXAMPLES

Example 1: Functional variants in FGG demonstrate protective associations for hearing disorders [00332] Variants in FGG were evaluated for associations with hearing disorders in approximately 452,000 individuals with genotype data from the UK Biobank cohort. Variants evaluated included: (1) rsl48685782, a rare (AAF=0.004) FGG missense variant (Alal08Gly; A108G), which has been experimentally characterized as a FGG and fibrinogen J, pQTL and (2) rs6063, a rare (AAF=0.005) FGG missense variant (Glyl91Arg; G191R) which is predicted to have a deleterious impact on the FGG protein and therefore on fibrinogen. Both variants may be hypomorphic or loss-of-fiinction variants that result in a decrease in the abundance or activity of the FGG gene product and therefore of fibrinogen. A FGG gene burden test which aggregated carriers of rsl48685782 and rs6063 was also evaluated.

[00333] The analyses resulted in identification of associations between the FGG variants and hearing disorders (Table 2). The rsl48685782 (A108G) variant, the rs6063 (G191R) variant and the FGG gene burden are all associated with protection from sensorineural hearing loss. Additionally, evaluated FGG variants are individually and/or collectively associated with decreased risk of tinnitus.

[00334] These results indicate that loss-of-function of FGG results in protection from a range of hearing disorders, including sensorineural hearing loss and tinnitus; and indicate that therapeutic inhibition of FGG may be useful for resulting in similar disease-protective effects or treatment effects.

Table 2: Protective variants

Example 2: Bioinformatic selection of sequences in order to identify therapeutic siRNAs to downmodulate expression of FGG mRNA

[00335] Screening sets were defined based on bioinformatic analysis. Therapeutic siRNAs were designed to target human FGG, and the FGG sequence of at least one toxicology-relevant species; in this case, non-human primates (NHP) including rhesus and cynomolgus monkeys. Drivers for the design of the screening set were predicted specificity of the siRNAs against the transcriptome of the relevant species as well as cross-reactivity between species. Predicted specificity in human, rhesus monkey, cynomolgus monkey, mouse, rat, rabbit, dog, gerbil, Syrian hamster, Chinese hamster, guinea pig, and naked mole rat was determined for sense (S) and antisense (AS) strands. These were assigned a “specificity score” which considered the likelihood of unintended downregulation of any other transcript by full or partial complementarity of an siRNA strand (up to 2 mismatches within positions 2-18) as well as the number and positions of mismatches. Thus, off-target(s) transcripts for antisense and sense strands of each siRNA were identified. In addition, the number of potential off-targets was used as an additional specificity factor in the specificity score. As identified, siRNAs with high specificity and a low number of predicted off-targets provide a benefit of increased targeting specificity.

[00336] In addition to selecting siRNA sequences with high sequence specificity to FGG mRNA, siRNA sequences within the seed region were analyzed for similarity to seed regions of known miRNAs. siRNAs can function in a miRNA like manner via base-pairing with complementary sequences within the 3’-UTR of mRNA molecules. The complementarity typically encompassed the 5’-bases at positions 2-7 of the miRNA (seed region). To circumvent siRNAs to act via functional miRNA binding sites, siRNA strands containing natural miRNA seed regions can be avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit and pig are referred to as “conserved”. Combining the “specificity score” with miRNA seed analysis yielded a “specificity category”. This was divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of the siRNA was assigned to a specificity category.

[00337] Specificity and species cross-reactivity was assessed for human, rhesus monkey, cynomolgus monkey, mouse, rat, rabbit, dog, gerbil, Syrian hamster, Chinese hamster, guinea pig and naked mole rat FGG. The analysis was based on a canonical siRNA design using 19 bases and 17 bases (without considering positions 1 and 19) for cross-reactivity. Full match as well as single mismatch analyses were included.

[00338] Analysis of the Genome Aggregation Database (gnomAD, available at gnomad.broadinstitute.org/) to identify siRNAs targeting regions with known SNPs was also carried out to identify siRNAs that may be non-fimctional in individuals containing the SNP. Information regarding the positions of SNPs within the target sequence as well as minor allele frequency (MAF) in case data was obtained in this analysis.

[00339] Initial analysis of the relevant FGG mRNA sequence revealed few sequences that fulfil the specificity parameters and at the same time target FGG mRNA in all of the analyzed relevant species. Therefore, it was decided to design independent screening subsets for the therapeutic siRNAs.

[00340] The siRNAs in these subsets were selected based on the ability to recognize at least the human, cynomolgus monkey, rhesus monkey FGG sequences. Therefore, the siRNAs in these subsets may be used to target human FGG in a therapeutic setting.

[00341] The number of siRNA sequences derived from human FGG mRNA (ENST00000404648, SEQ ID NO: 3621) without consideration of specificity or species cross-reactivity was 1742 (sense and antisense strand sequences included in SEQ ID NOS: 1-3484).

[00342] Prioritizing sequences for target specificity, species cross-reactivity, miRNA seed region sequences and SNPs as described above yielded subset A. Subset A includes 319 siRNAs whose base sequences are shown in Table 3.

Table 3: Subset A siRNAs

[00343] The siRNAs in subset A were selected to have the following characteristics: • Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG

• Specificity category: For human and NHP: AS2 or better, SS3 or better

• miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species

• Off-target frequency: <30 human off-targets matched with 2 mismatches in antisense strand

• SNPs: siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)

[00344] The siRNA sequences in subset A were selected for more stringent specificity to yield subset

B. Subset B includes 318 siRNAs whose base sequences are shown in Table 4.

Table 4: Subset B siRNAs

[00345] The siRNAs in subset B were selected to have the following characteristics:

• Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG

• Specificity category: For human and NHP: AS2 or better, SS3 or better

• Off-target frequency: <20 human off-targets matched with 2 mismatches in antisense strand

• SNPs: siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)

[00346] The siRNA sequences in subset B were further selected for absence of seed regions in the AS strand that are identical to a seed region of known human miRNA to yield subset C. Subset C includes 221 siRNAs whose base sequences are shown in Table 5.

Table 5: Subset C siRNAs

[00347] The siRNAs in subset C have the following characteristics:

• Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG

• Specificity category: For human and NHP: AS2 or better, SS3 or better

• miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS strand: seed region not identical to seed region of known human miRNA

• Off-target frequency: <30 human off-targets matched with 2 mismatches by antisense strand

• SNPs: siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)

[00348] The siRNA sequences in subset C were also selected for absence of seed regions in the AS or

S strands that are identical to a seed region of known human miRNA to yield subset D. Subset D includes 147 siRNAs whose base sequences are shown in Table 6.

Table 6. Subset D siRNAs

[00349] The siRNAs in subset D were selected to have the following characteristics:

• Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG

• Specificity category: For human and NHP: AS2 or better, SS3 or better

• miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS+SS strand: seed region not identical to seed region of known human miRNA

• Off-target frequency: <20 human off-targets matched with 2 mismatches by antisense strand

• SNPs: siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)

[00350] Subset E includes 53 siRNAs. The siRNAs in subset E include siRNAs from subset A and additional siRNAs that were tested in vitro (see, e.g., Table 7).

Table 7. Subset E siRNAs

[00351] In some cases, the sense strand of any of the siRNAs of subset E comprises siRNA with a particular modification pattern. In this example modification pattern, position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification. Where a “2’F modification” is denoted, it is intended to mean that a 2’F is included. In this example modification pattern, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’0Me modification. Where a “2’0Me modification” is denoted, it is intended to mean that a 2’0Me is included. In this example modification pattern, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. In this example modification pattern, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with the 2’F modification in the sense strand. In this example modification pattern, when position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines ’re in adjacent positions so that there would be not three 2'F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In this example modification pattern, when there are >2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.

[00352] In this example modification pattern, when position 9 of the sense strand is a purine, then all purines in the sense strand have the 2’0Me modification. In this example modification pattern, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. In this example modification pattern, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with the 2’F modification in the sense strand. In this example modification pattern, when position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In this example modification pattern, when there are >2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs of subset E comprises a modification pattern which conforms to these sense strand rules (Table 8A).

[00353] In some cases, the antisense strand of any of the siRNAs of subset E comprises modification pattern 9AS (Table 8A). The siRNAs in subset E may comprise any other modification pattem(s).

Table 8A. Modified siRNA sequences

[00354] In Table 8A, Nf (Af, Cf, Gf, Uf, or Tf) is a 2’-fluoro-modified nucleoside, n (a, c, g, u, or t) is a 2’-0-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

[00355] Any siRNA among any of subsets A-E may comprise any modification pattern described herein. If a sequence is a different number of nucleotides in length than a modification pattern, the modification pattern may still be used with the appropriate number of additional nucleotides added 5’ or 3’ to match the number of nucleotides in the modification pattern. For example, if a sense or antisense strand of the siRNA among any of subsets A-E comprises 19 nucleotides, and a modification pattern comprises 21 nucleotides, UU may be added onto the 5’ end of the sense or antisense strand.

Using a different algorithm for analyzing siRNA specificity, an additional bioinformatically selected set of siRNAs was generated. Prioritizing sequences for target specificity, species cross-reactivity, miRNA seed region sequences and SNPs as described above yields subset G. Subset G contains 131 siRNAs whose base sequences are shown in Table 8B.

Table 8B: Subset G siRNAs

[00356] The siRNAs in subset G had the following characteristics:

• Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG

• Specificity category: For human and NHP: AS2 or better, SS3 or better • miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species

• SNPs: siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)

Example 3: Screening FGG siRNAs for activity in Hep 3B2.1-7 cells in culture

[00357] Chemically modified FGG siRNAs cross reactive for at least human and non-human primates will be assayed for FGG mRNA knockdown activity in cells in culture. Hep 3B2.1-7 cells (ATCC® catalog# HB-8064) will be seeded in 96-well tissue culture plates at a cell density of 7,500 cells per well in EMEM media (VWR catalog# 76000-922) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37°C in an atmosphere without supplemental carbon dioxide. The FGG siRNAs will be individually transfected into Hep 3B2. 1-7 cells in duplicate wells at 1 nM and 10 nM final concentration using 0.3 pL Lipofectamine RNAiMax (Fisher, catalog# 13778150) in 5 pl Opti-MEM (Thermo Fisher, catalog# 31985070) per well. Silencer Select Negative Control #3 (ThermoFisher, Catalog# 4392420 ID s51788) will be transfected at 1 nM and 10 nM final concentrations as a control. A positive control siRNA (ThermoFisher, Catalog#) will be transfected at 1 nM and 10 nM final concentrations. After incubation for 48 hours at 37°C, total RNA will be harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, catalog# A35374) according to the manufacturer’s instructions. The level of FGG mRNA from each well will be measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml). The level of PPIA mRNA will be measured using TaqMan Gene Expression Assay (ThermoFisher, assay# Hs99999904_ml) and used to determine relative FGG mRNA levels in each well using the delta-delta Ct method. All data will be normalized to relative FGG mRNA levels in untreated Hep 3B2.1-7 cells. Identification of siRNAs targeting FGG that reduce FGG expression is anticipated.

Example 4: Determining the IC50 of FGG siRNAs

[00358] The IC50 values for knockdown of FGG mRNA by select FGG siRNAs will be determined in Hep 3B2.1-7 cells. The siRNAs will be assayed individually in triplicate at 30 nM, 10 nM, 3 nM, 1 nM and 0.3 nM, 0.1 nM and 0.03 nM. Hep 3B2.1-7 cells (ATCC® catalog# HB-8064) will be seeded in 96- well tissue culture plates at a cell density of 7,500 cells per well in EMEM media (VWR catalog# 76000- 922) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37°C in an atmosphere without supplemental carbon dioxide. The FGG siRNAs will be individually transfected using 0.3 pL Lipofectamine RNAiMax (Fisher, catalog# 13778150) in 5 pl Opti- MEM (Thermo Fisher, catalog# 31985070) per well. After incubation for 48 hours at 37°C, total RNA will be harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog# A35374) according to the manufacturer’s instructions. The level of FGG mRNA from each well will be measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml). The level of PPIA mRNA will be measured using TaqMan Gene Expression Assay (ThermoFisher, assay# Hs99999904_ml) and used to determine relative FGG mRNA levels in each well using the delta-delta Ct method. All data will be normalized to relative FGG mRNA levels in untreated Hep 3B2.1-7 cells. Curve fit will be accomplish using the [inhibitor] vs. response (three parameters) function in GraphPad Prism software.

Example 5: ASO-mediated knockdown of FGG in HEPG2 cell line

[00359] ASOs targeted to the FGG mRNA that downregulate levels of FGG mRNA leading to a decrease in FGG secretion, when administered to the cultured human hepatocyte cell line, HepG2.

[00360] On Day 0, the HEPG2 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mb per well.

[00361] On Day 1, the FGG ASO and negative control ASO master mixes are prepared. The FGG ASO master mix contains 350 pl of Opti-MEM (ThermoFisher Cat. No. 4427037 - sl288 Lot No. AS02B02D) and 3.5 pl of a FGG ASO (10 pM stock). The negative control ASO master mix contains 350 pl of Opti-MEM and 3.5 pl of negative control ASO (ThermoFisher Cat. No. 4390843, 10 uM stock). Next, 3 pl of TransIT-X2 (Minis Cat. No. MIR-6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 51 pl of the appropriate master mix + TransIT-X2 is added to duplicate wells of HEPG2 cells with a final ASO concentration of 10 nM. [00362] On Day 3, 48 hours post transfection, media is collected and mixed with protein lysis buffer containing protease and phosphatase inhibitors, and the cells are lysed using the Cells -to-Ct kit according to the manufacturer’s protocol (ThermoFisher Cat. No. 4399002). For the Cells-to-Ct, cells are washed with 50 pl using cold IX PBS and lysed by adding 49.5 pl of Lysis Solution and 0.5 pl Dnase I per well and pipetting up and down 5 times and incubating for 5 minutes at room temperature. The Stop Solution (5 pl/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes. The reverse transcriptase reaction is performed using 22.5 pl of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/FGG using a BioRad CFX96 Cat. No. 1855195). For the protein quantification, equivalent quantities (30-50 pg) of protein are separated by 10% SDS polyacrylamide gels and transferred to polyvinylidene fluoride membranes. Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibody at dilutions specified by the manufacturer. Next, the membranes are washed three times in TBST and incubated with the corresponding horseradish peroxidase conjugated secondary antibody at 1:5,000 dilution for 1 hr. Bound secondary antibody is detected using an enhanced chemiluminescence system. The primary immunoblotting antibody is an anti-FGG antibody (Abeam, Cambridge, UK).

[00363] A decrease in FGG mRNA expression in the HEPG2 cells is expected after transfection with the FGG ASO compared to FGG mRNA levels in HEPG2 cells transfected with the non-specific control ASO 48 hours after transfection. There is an expected decrease in the amount of FGG secreted protein, measured by quantifying the amount of FGG protein in media of HEPG2 cells transfected with the FGG ASO relative to the amount of FGG protein in media of HEPG2 cells transfected with a non-specific control ASO 48 hours after transfection. These results show that the FGG ASOs elicit knockdown of FGG mRNA in HEPG2 cells and that the decrease in FGG expression is correlated with a decrease in FGG protein secretion.

Example 6: Determining the activity of species cross-reactive siRNAs targeting FGG in mice [00364] Five groups (n=4/group) of 8 week old male ICR mice (Harlan) were utilized in this study. On Study Day -4, all animals were anesthetized and blood was collected via the submandibular vein and into tubes containing citrate for collection of plasma. Plasma fibrinogen levels were measured use the Clauss method (IDEXX Laboratories, Test# 6308) and by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT). On Study Day 0, Group 1 mice were injected subcutaneously with 100 pl of sterile PBS, Group 2 mice were subcutaneously injected with 200 pg of ETD01592 (sense strand SEQ ID NO: 3591; antisense strand SEQ ID NO: 3595) in 100 pl of sterile PBS, Group 3 mice were subcutaneously injected with 200 pg ETD01593 (sense strand SEQ ID NO: 3592; antisense strand SEQ ID NO: 3596) in 100 pl of sterile PBS, Group 4 mice were subcutaneously injected with 200 pg of ETD01594 (sense strand SEQ ID NO: 3593; antisense strand SEQ ID NO: 3597) in 100 pl PBS, and Group 5 mice were subcutaneously injected with 200 pg of ETD01595 (sense strand SEQ ID NO: 3594; antisense strand SEQ ID NO: 3598) in 100 pl PBS. On Study Day 10, the animals from all Groups were anesthetized, bled via cardiac puncture to collect serum and plasma, and then euthanized. A liver sample was collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). Serum clinical chemistry analyses were performed (IDEXX Laboratories, Test# 60513) and plasma fibrinogen levels were measured as described for the Day -4 samples. The liver samples were processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice (Group 1) using the delta-delta Ct method.

[00365] The results of the liver mRNA analyses are shown in Table 9. Animals treated ETD01592 (Group 2), ETD01593 (Group 3), ETD01594 (Group 4), or ETD01595 (Group 4) showed decreased liver FGG mRNA levels compared with mice injected with PBS (Group 1). The results of the plasma fibrinogen analyses are shown in Table 10. Animals treated with ETD01592 (Group 2), ETD01593 (Group 3), ETD01594 (Group 4), or ETD01595 (Group 5) showed decreased plasma fibrinogen levels as measured by the Clauss method or by ELISA compared with mice injected with PBS (Group 1). The results from the clinical chemistry indicated all the siRNAs were generally well tolerated (Table 11). Table 9: Day 10 FGG mRNA liver levels in mice treated with siRNAs targeting FGG

Table 10. Day 10 plasma fibrinogen levels in mice treated with siRNAs targeting FGG

*Clauss method LLOQ <0.5 mg/dL

Table 11. Clinical chemistry results after injection of mice with 200 pg of ETD01592, ETD01593,

ETD01594 or ETD01595

Example 7: Determining the activity of siRNAs targeting FGG in mice at low dose levels

[00366] Nine groups (n=3/group) of 8 week old male ICR mice (Harlan) were utilized in this study. On Study Day 0, mice in Group 1 were injected subcutaneously with 100 pl of sterile PBS, mice in Groups 2 and 3 were subcutaneously injected with 20 pg or 60 pg of ETD01592, respectively (sense strand SEQ ID NO: 3591; antisense strand SEQ ID NO: 3595) in 100 pl of sterile PBS, mice in Groups 4 and 5 were subcutaneously injected with 20 pg or 60 pg of ETD01593, respectively (sense strand SEQ ID NO: 3592; antisense strand SEQ ID NO: 3596) in 100 pl of sterile PBS, mice in Groups 6 and 7 were subcutaneously injected with 20 pg or 60 pg of ETD01594, respectively (sense strand SEQ ID NO: 3593; antisense strand SEQ ID NO: 3597) in 100 pl PBS, and mice in Groups 8 and 9 were subcutaneously injected with 20 pg or 60 pg of ETD01595, respectively (sense strand SEQ ID NO: 3594; antisense strand SEQ ID NO: 3598) in 100 pl PBS. On Study Day 10, the animals from all groups were anesthetized, bled via cardiac puncture to collect serum and plasma, and then euthanized. A liver sample was collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). Plasma fibrinogen levels were measured by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT). Plasma prothrombin time (PT) and activated partial thromboplastin time (aPTT) (IDEXX Laboratories, Test# 6308) and serum clinical chemistry measurements were also performed (IDEXX Laboratories, Test# 60513). The liver samples were processed in homogenization buffer (Maxwell RSC simply RNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice (Group 1) using the delta-delta Ct method.

[00367] The results of the liver mRNA analyses are shown in Table 12. Animals treated with 20 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased liver FGG mRNA levels compared with mice injected with PBS. Animals treated with 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased liver FGG mRNA levels compared with mice injected with 20 pg of those siRNAs or with mice injected with PBS. The results of the plasma fibrinogen ELISA are shown in Table 13. Animals treated with 20 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased plasma fibrinogen protein levels compared with mice injected with PBS. Animals treated with 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased plasma fibrinogen protein levels compared with mice injected with 20 pg of those siRNAs or with mice injected with PBS. The results of the PT and aPTT measurements in animals treated with 20 pg and 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 are shown in Table 14. The results from the clinical chemistry indicate that all the siRNAs were generally well tolerated at these dose levels (Table 15).

Table 12. FGG mRNA liver levels in mice treated with 20 pg or 60 pg of ETD01592, ETD01593, ETD01594 or ETD01595.

Table 13. Plasma fibrinogen levels in mice treated with 20 pg or 60 pg of ETD01592, ETD01593, ETD01594 or ETD01595.

Table 14. PTT and aPTT in mice treated with 20 pg or 60 pg of ETD01592, ETD01593, ETD01594 or ETD01595.

Table 15. Clinical chemistry results after injection of mice with 20 pg or 60 pg of ETD01592, ETD01593, ETD01594 or ETD01595.

Example 8: Screening FGG siRNAs for activity in Huh7 cells in culture

[00368] Chemically modified FGG siRNAs cross-reactive for at least human and non-human primates were assayed for FGG mRNA knockdown activity in cells in culture. Huh7 cells (Xenotech catalog# JCRB0403) were seeded in 96-well tissue culture plates at a cell density of 20,000 cells per well in DMEM media (VWR catalog# 02-0100-0500) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37°C in an atmosphere containing 5% carbon dioxide. The FGG siRNAs were individually transfected into Huh7 cells in duplicate wells at 1 nM and 10 nM final concentration using 0.2 pL Lipofectamine RNAiMax (Fisher, catalog# 13778150) in 5 pl Opti- MEM (Thermo Fisher, catalog# 31985070) per well. Silencer Select Negative Control #1 (ThermoFisher, catalog# 4390843) was transfected at 1 nM and 10 nM final concentrations as a negative control. Positive control siRNAs targeting FGG (ThermoFisher, catalog# 4392420, Assay IDs s5179, s5180) were transfected at 1 nM and 10 nM final concentrations. After incubation for 48 hours at 37°C, total RNA was harvested from each well using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, catalog# A35374) according to the manufacturer’s instructions. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The level of FGG mRNA from each well was measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan® Fast Advanced Master Mix (Fisher Scientific catalog# 44-445-58), TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml) and TaqMan Gene Expression Assay for human PPIA (ThermoFisher, assay# Hs99999904_ml). The relative FGG mRNA levels in each well was calculated using the delta-delta Ct method. All data were normalized to relative FGG mRNA levels in untreated Huh7 cells. Results are shown in Table 16.

Table 16: Knockdown activity of FGG-specific siRNAs at 1 nM and 10 nM in Huh7 cells

Example 9: Determining the IC50 of FGG siRNAs in Huh7 cells in culture

[00369] The IC50 values for knockdown of FGG mRNA by select FGG siRNAs were determined in Huh7 cells. The siRNAs were assayed individually in triplicate at 30 nM, 10 nM, 3 nM, 1 nM and 0.3 nM, 0.1 nM and 0.03 nM. Huh7 cells (Xenotech catalog# JCRB0403) were seeded in 96-well tissue culture plates at a cell density of 20,000 cells per well in DMEM media (VWR catalog# 02-0100-0500) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37°C in an atmosphere supplemented with 5% carbon dioxide. The FGG siRNAs will be individually transfected using 0.2 pL Lipofectamine RNAiMax (Fisher, catalog# 13778150) in 5 pl Opti- MEM (Thermo Fisher, catalog# 31985070) per well. The positive control siRNA targeting FGG (ThermoFisher, catalog# 4392420, Assay ID s5179) was included as a comparator. After incubation for 48 hours at 37°C, total RNA was harvested from each well using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, catalog# A35374) according to the manufacturer’s instructions. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The level of FGG mRNA from each well was measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan® Fast Advanced Master Mix (Fisher Scientific catalog# 44-445-58), TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml) and TaqMan Gene Expression Assay for human PPIA (ThermoFisher, assay# Hs99999904_ml). The relative FGG mRNA levels in each well was calculated using the delta-delta Ct method. All data were normalized to relative FGG mRNA levels in untreated Huh7 cells. Curve fit was accomplish using the [inhibitor] vs. response (three parameters) function in GraphPad Prism software. Results are shown in Table 17. Table 17. IC50 Values of FGG siRNAs in Human Huh7 Cells

Example 10. Optimization of siRNAs targeting human, cynomolgus monkey, rat and mouse FGG in mice

[00370] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 18A, where “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 18B.

[00371] Six to eight week old female mice (strain ICR, n=4) were given a subcutaneous injection on Day 0 of a single 20 pg or 60 pg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

[00372] Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 19.

[00373] On Day 0 (prior to dosing), 7 and Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 20.

[00374] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 21.

Table 18A. Example siRNA Sequences

Table 18B. Example siRNA BASE Sequences

Table 19. Relative FGG mRNA Levels in Livers of Mice

Table 20. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 21. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 11. Optimization of siRNAs from position 1218 targeting human, cynomolgus monkey, rat and mouse FGG in mice

[00375] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 22A, where “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 22B.

[00376] Six to eight week old female mice (strain ICR, n=4) were given a subcutaneous injection on Day 0 of a single 60 pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control.

[00377] Mice were euthanized on Day 10 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 23.

[00378] On Day 0 (prior to dosing), 7 and Day 10 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 24. [00379] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 25. Table 22A. Example siRNA Sequences

Table 22B. Example siRNA BASE Sequences

Table 23. Relative FGG mRNA Levels in Livers of Mice

Table 24. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 25. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 12. Testing differentially modified GalNAc siRNAs targeting human, cynomolgus monkey, rat and mouse FGG in mice

[00380] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL1 or ETL17. The siRNA sequences are shown in Table 26A, where “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 26B.

[00381] Six to eight week old female mice (strain ICR, n=4) were given a subcutaneous injection on Day 0 of a single 60 pg or 120 pg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

[00382] Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 27.

[00383] On Day 0 (prior to dosing), 7 and Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 28. [00384] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 29. Mice injected with ETD01811, ETD01818, and ETD01819 had an increase in PT and APPT times on Day 7 and 14 relative to mice receiving PBS.

[00385] On Days 0, 7, and 14 blood was collected into tubes with no anti-coagulant serum collected. Clinical chemistry parameters containing ALT, ALP, TBIL, and BUN were analyzed at IDEXX Laboratories (IDEXX Laboratories, Test# 62849). Results are shown in Table 30.

Table 26A. Example siRNA Sequences

Table 26B. Example siRNA Base Sequences

Table 27. Relative FGG mRNA Levels in Livers of Mice

Table 28. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 29. PT and APTT Times in Mice treated with siRNAs targeting FGG

Table 30. Clinical Chemistry in Mice treated with siRNAs targeting FGG

Example 13. Screening siRNAs from position 352 targeting human, cynomolgus monkey, rat and mouse FGG in mice

[00386] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 31A, where “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. Base sequences are listed in Table 31B.

[00387] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 40 pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control.

[00388] Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 32.

Table 31A. Example siRNA Sequences

Table 31B. Example siRNA Base Sequences

Table 32. Relative FGG mRNA Levels in Livers of Mice

Example 14. Screening siRNAs targeting human, cynomolgus monkey, rat and mouse FGG in mice [00389] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL1 or ETL17. The siRNA sequences are shown in Table 33A, where “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 33B.

[00390] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60 pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control.

[00391] Mice were euthanized on Day 10 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 34.

[00392] On Day 0 (prior to dosing), Day 10 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 35. [00393] On Day lOblood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 36.

Table 33A. Example siRNA Sequences

Table 33B. Example siRNA Base Sequences

Table 34. Relative FGG mRNA Levels in Livers of Mice

Table 35. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 36. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 15. Screening of siRNAs from positions 352 and 1218 targeting human FGG mRNA in mice transfected with AAV8-TBG-h-FGG

[00394] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey, rat and mouse FGG mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 37A, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 37B. [00395] Six to eight week old female mice (C57B1/6) were injected with 10 pl of a recombinant adeno-associated virus 8 (AAV8) vector (2.1 x 10E13 genome copies/mL) by the retroorbital route on Day -14. The recombinant AAV8 contains the open reading frame and a portion of the 5’ and 3’UTRs of the human FGG sequence (ENST00000404648) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-FGG). On Day 0, infected mice (n=3) were given a subcutaneous injection of a single 60 pg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

[00396] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human FGG (ThermoFisher, assay# Hs00241038_ml),or mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g 1 ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Mice injected with ETD01592, ETD01594, ETD01745, ETD01747, ETD01748, and ETD01750 had substantial reductions in mean liver mouse FGG mRNA on Day 14 relative to mice receiving PBS. Results are shown in Table 38. Mice injected with ETD01592, ETD01594, ETD01745, ETD01747, ETD01748, and ETD01750 had substantial reductions in mean liver human FGG mRNA on Day 14 relative to mice receiving PBS. Results are shown in Table 39.

[00397] On Day 0 (prior to dosing), 7 and Day 10 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 40. [00398] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 41. On average mice injected with ETD01592, ETD01594, ETD01745, ETD01747, ETD01748, and ETD01750 had no change in PT and APPT times on Day 14 relative to mice receiving PBS.

Table 37A. Example siRNA Sequences

Table 37B. Example siRNA Base Sequences

Table 38. Relative mouse FG mRNA Levels in Livers of Mice

Table 39. Relative human FGG mRNA Levels in Livers of Mice

Table 40. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 41. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 16. Screening of siRNAs targeting human FGG mRNA in mice transfected with AAV8- TBG-h-FGG

[00399] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey, rat and mouse FGG mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 42A, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 42B. [00400] Six to eight week old female mice (C57B1/6) were injected with 10 pl of a recombinant adeno-associated virus 8 (AAV8) vector (2.1 x 10E13 genome copies/mL) by the retroorbital route on Day 14. The recombinant AAV8 contains the open reading frame and a portion of the 5’ and 3’UTRs of the human FGG sequence (ENST00000404648) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-FGG). On Day 0, infected mice (n=4) were given a subcutaneous injection of a single 60 pg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

[00401] Mice were euthanized on Day 10 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human FGG (ThermoFisher, assay# Hs00241038_ml),or mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g 1 ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Mice injected with ETD01818, ETD01839, ETD01841, ETD01849, ETD01852, had greatest reductions in mean liver mouse FGG mRNA on Day 10 relative to mice receiving PBS. Results are shown in Table 43. Mice injected with ETD01818, ETD01839, ETD01841, ETD01849, and ETD01856 had greatest reductions in mean liver human FGG mRNA on Day 10 relative to mice receiving PBS. Results are shown in Table 44.

[00402] On Day 0 (prior to dosing), 7 and Day 10 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 45. [00403] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 46. Mice injected with ETD01818, ETD01839, ETD01840, and ETD01841 had an increase in PT and APPT times on Day 7 and 10 relative to mice receiving PBS.

Table 42A. Example siRNA Sequences

Table 42B. Example siRNA Base Sequences

Table 43. Relative mouse FGG mRNA Levels in Livers of Mice

Table 44. Relative human FGG mRNA Levels in Livers of Mice

Table 45. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 46. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 17. Screening of siRNAs targeting human FGG mRNA in mice transfected with AAV8- TBG-h-FGG

[00404] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey, rat and mouse FGG mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 47A, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 47B.

[00405] Six to eight week old female mice (C57B1/6) were injected with 10 pl of a recombinant adeno-associated virus 8 (AAV8) vector (2.4 x 10E13 genome copies/mL) by the retroorbital route on Day -14. The recombinant AAV8 contains the open reading frame and a portion of the 5’ and 3’UTRs of the human FGG sequence (ENST00000404648) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-FGG). On Day 0, infected mice (n=5) were given a subcutaneous injection of a single 60 pg or 100 pg dose of a GalNAc- conjugated siRNA or PBS as vehicle control.

[00406] Mice were euthanized on Day 10 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human FGG (ThermoFisher, assay# Hs00241038_ml),or mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Mice injected with ETD01818, ETD01839, and ETD01841 had substantial reductions in mean liver mouse FGG mRNA on Day 10 relative to mice receiving PBS at both 60 pg and 100 pg doses. Results are shown in Table 48. Mice injected with ETD01818, ETD01839, and ETD01841 had substantial reductions in mean liver human FGG mRNA on Day 10 relative to mice receiving PBS at both 60 pg and 100 pg doses. Results are shown in Table 49. [00407] On Day 0 (prior to dosing), 7 and Day 10 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 50.

[00408] On Day 14 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at IDEXX Laboratories (IDEXX Laboratories, Test# 6005). Results are shown in Table 51. Mice injected with ETD01818, ETD01839, and ETD01841 had dose dependent increase in PT and APPT times on Day 7 and 10 relative to mice receiving PBS.

Table 47A. Example siRNA Sequences

Table 47B. Example siRNA BASE Sequences

Table 48. Relative mouse FGG mRNA Levels in Livers of Mice

Table 49. Relative human FGG mRNA Levels in Livers of Mice

Table 50. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 51. PT and APTT Times in Mice treated with siRNAs targeting FGG

Example 18. Determining the activity of siRNAs targeting FGG in non-human primates

[00409] This study was conducted at Pharmalegacy Laboratories, Inc. on behalf of Empirico. Three groups (n=3/group) of 4-7 year old male cynomolgus monkeys (Zhaoqing Chuangyao Biotechnology Co., Ltd and Guangzhou Xianngguan Biotechnology Co., Ltd) were utilized for this study.

[00410] On Study Day 0, Group 1 cynomolgus monkeys were injected with 2mg/kg ETD01839 (sense strand SEQ ID NO: 3652; antisense strand SEQ ID NO: 3688) at a concentration of lOmg/mL, Group 2 cynomolgus monkeys were injected with 2mg/kg ETD01841 (sense strand SEQ ID NO: 3654; antisense strand SEQ ID NO: 3690) at a concentration of lOmg/mL, Group 3 cynomolgus monkeys were injected with 2mg/kg ETD01926 (sense strand SEQ ID NO: 3675; antisense strand SEQ ID NO: 3711) at a concentration of lOmg/mL. All animals had no abnormal clinical symptoms and well tolerated with single subcutaneous dose at 2 mg/kg of ETD01839, ETD01841 and ETD01926.

[00411] On Study Days -8, -2, 7, 14, 21 and Day 28 body weights were recorded. Results are shown in Table 52.

Table 52. Body Weights in Cynomolgus Monkeys treated with siRNAs targeting FGG

[00412] On Study Day -2 and Day 28, the animals were anesthetized with Zoletil (1.5 - 5.0 mg/kg, i.m.) and xylazine (0.5 - 2.0 mg/kg, i.m.) and 3-4mg liver biopsy was collected. The biopsy was then placed in 10 v/v RNAlater in 20 seconds and stored for 24 hrs at 4°C, the RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020) was then removed and the liver tissue was stored in freezer until they were shipped to Empirico. There were no abnormal clinical observations for all animals after liver biopsy collection on Day -2 or Day 28. The liver samples were processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative level of FGG mRNA in each Study Day 28 liver biopsy sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for cynomolgus FGG (ThermoFisher, assay# Mf02793821_ml) and the cynomolgus housekeeping gene ACTB (ThermoFisher, assay# Mf0435434 l_g I ). and then normalized to the mean value of the Study Day -2 pre-dose liver biopsy using the delta-delta Ct method. Animals treated with ETD01839, ETD01841 or ETD01926 showed decreased liver FGG mRNA levels on Study Day 28 compared to liver biopsies obtained from the same animals on Study Day -2. Results are shown in Table 53.

Table 53. Day 28 FGG mRNA liver levels in Cynomolgus Monkeys treated with siRNAs targeting FGG

[00413] On Study Days -2 ,-8, 7, 14, 21, and Day 28 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT at Pharmalegacy Laboratories, Inc. and the remaining plasma samples were stored in a freezer until they were shipped to Empirico. Plasma sample were then transferred to IDEXX Laboratories and plasma fibrinogen levels were measured by the Clauss method (IDEXX Laboratories, Test# 6308). Results are shown in Tables 54 and 55. Animals treated with ETD01839, ETD01841 or ETD01926 showed a decrease in plasma fibrinogen starting on Study Day 7 though Study Day 28 when compared to Study Day -8 and Study Day -2, prior to treatment. Results are shown in Table 56. Table 54. Prothrombin time in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 55. Activated Partial Thromboplastin time in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 56. Plasma fibrinogen levels in Cynomolgus Monkeys treated with siRNAs targeting FGG

[00414] On Study Days -8, -2, 7, 14, 21, and Day 28 blood was collected into tubes with no anticoagulant and serum collected. Clinical chemistry parameters containing ALT, AST, ALP, DBIL, TBIL, GLU, UREA, CREA, TP and CGT were analyzed at Pharmalegacy Laboratories, Inc.

[00415] Results are shown in Tables 57-65B. Table 57. Clinical Chemistry ALT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 58. Clinical Chemistry AST results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 59. Clinical Chemistry ALP results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 60. Clinical Chemistry DBIL results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 61. Clinical Chemistry TBIL results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 62. Clinical Chemistry GLU results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 63. Clinical Chemistry UREA results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 64. Clinical Chemistry CREA results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 65A. Clinical Chemistry TP results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 65B. Clinical Chemistry CGT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Example 19. Discovery toxicity siRNAs targeting human, cynomolgus monkey, rat and mouse FGG in mice

[00416] Several siRNAs designed to be cross-reactive with human, cynomolgus monkey and mouse FGG mRNA were tested for toxicity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 66A, where Nf is a 2’-fluoro-modified nucleoside, n is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences are shown in Table 66B

[00417] Six to eight week old female mice (strain ICR, n=4) were given a subcutaneous injection on Day 0, 7, and Day 14 of a 200 pg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

[00418] Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Perce llys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving PBS. Results are shown in Table 67.

[00419] On Day 0 (prior to dosing) and Day 21 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT). Results are shown in Table 68. [00420] On Day 2, 9, and Day 21 blood was collected into tubes with no anti -coagulant and serum collected. Clinical chemistry parameters containing ALT, AST, ALP, TBIL, GLU, BUN, and CREAT were analyzed at IDEXX Laboratories (IDEXX Laboratories, Test# 62849). Results are shown in Tables 69-74.

Table 66A. Example siRNA Sequences

Table 66B. Example siRNA BASE Sequences

Table 67. Relative FGG mRNA Levels in Livers of Mice

Table 68. Fibrinogen Levels in Plasma of Mice treated with siRNAs targeting FGG

Table 69. Clinical Chemistry ALT in Mice treated with siRNAs targeting FGG

Table 70. Clinical Chemistry AST in Mice treated with siRNAs targeting FGG

Table 71. Clinical Chemistry ALP in Mice treated with siRNAs targeting FGG

Table 72. Clinical Chemistry TBILI in Mice treated with siRNAs targeting FGG

Table 73. Clinical Chemistry BUN in Mice treated with siRNAs targeting FGG

Table 74. Clinical Chemistry BUN in Mice treated with siRNAs targeting FGG

Example 20: Determining the activity of species cross-reactive siRNAs targeting FGG in mice [00421] 3 groups (n=4/group) of 8-week-old male ICR mice (Invigo) were utilized in this study. On

Study Day 0, Group 1 mice were injected subcutaneously with 100 pl of sterile PBS, Group 2 mice were subcutaneously injected with 60 pg of ETD01811 in 100 pl of sterile PBS, and Group 3 mice were subcutaneously injected with 200 pg ETD01818 in 100 pl of sterile PBS. On Study Day 14, the animals from all Groups were anesthetized and then euthanized. A liver sample was collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples were processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice (Group 1) using the delta-delta Ct method.

[00422] The results of the liver mRNA analyses are shown in Table 75 below. Animals treated with

ETLl-targeted siRNA (ETD01811, Group 2) had 78% relative knockdown while ETL17-targeted siRNA (ETD01818, Group 3) had 83% knockdown of liver FGG mRNA levels compared with mice injected with PBS (Group 1).

Table 75: Day 14 FGG mRNA liver levels in mice treated with siRNAs targeting FGG

Example 21: Oligonucleotide Synthesis

[00423] Oligonucleotides such as siRNAs may be synthesized according to phosphoramidite technology on a solid phase. For example, a K&A oligonucleotide synthesizer may be used. Syntheses may be performed on a solid support made of controlled pore glass (CPG, 500 A or 600 A, obtained from AM Chemicals, Oceanside, CA, USA). All 2'-0me and 2’-F phosphoramidites may be purchased from Hongene Biotech (Union City, CA, USA). All phosphoramidites may be dissolved in anhydrous acetonitrile (100 mM) and molecular sieves (3 A) may be added. 5 -Benzylthio- IH-tetrazole (BTT, 250 mM in acetonitrile) or 5-Ethylthio-lH-tetrazole (ETT, 250 mM in acetonitrile) may be used as activator solution. Coupling times may be 9-18 min (e.g., with a GalNAc such as ETL17), 6 min (e.g., with 2'0me and 2'F). In order to introduce phosphorothioate linkages, a 100 mM solution of 3 -phenyl- 1,2,4- dithiazoline-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous acetonitrile may be employed.

[00424] After solid phase synthesis, the dried solid support may be treated with a 1 : 1 volume solution of 40 wt. % methylamine in water and 28% ammonium hydroxide solution (Aldrich) for two hours at 30° C. The solution may be evaporated and the solid residue may be reconstituted in water and purified by anionic exchange HPLC using a TKSgel SuperQ-5PW 13u column. Buffer A may be 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B may be the same as buffer A with the addition of 1 M sodium chloride. UV traces at 260 run may be recorded. Appropriate fractions may be pooled then desalted using Sephadex G-25 medium.

[00425] Equimolar amounts of sense and antisense strand may be combined to prepare a duplex. The duplex solution may be prepared in O. l xPBS (Phosphate-Buffered Saline, l x, Gibco). The duplex solution may be annealed at 95° C. for 5 min, and cooled to room temperature slowly. Duplex concentration may be determined by measuring the solution absorbance on a UV-Vis spectrometer at 260 nm in O.l xPBS. For some experiments, a conversion factor may be calculated from an experimentally determined extinction coefficient. Example 22: GalNAc ligand for hepatocyte targeting of oligonucleotides

[00426] Without limiting the disclosure to these individual methods, there are at least two general methods for atachment of multivalent N-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid or solution-phase conjugations. GalNAc ligands may be atached to solid phase resin for 3’ conjugation or at the 5’ terminus using GalNAc phosphoramidite reagents. GalNAc phosphoramidites may be coupled on solid phase as for other nucleosides in the oligonucleotide sequence at any position in the sequence.

Reagents for GalNAc conjugation to oligonucleotides are shown in Table 76.

Table 76. GalNAc Conjugation Reagents

[00427] In solution phase conjugation, the oligonucleotide sequence — including a reactive conjugation site — is formed on the resin. The oligonucleotide is then removed from the resin and GalNAc is conjugated to the reactive site. [00428] The carboxy GalNAc derivatives may be coupled to amino-modified oligonucleotides. The peptide coupling conditions are known to the skilled in the art using a carbodiimide coupling agent like DCC (N,N'-Dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide) or EDC.HC1 (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and an additive like HOBt (1- hydroxybenztriazole), HOSu (N -hydroxy succinimide), TBTU (N,N,N',N'-Tetramethyl-O-(benzotriazol-l- yl)uronium tetrafluoroborate, HBTU (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) or HO At (l-Hydroxy-7-azabenzotriazole and common combinations thereof such as TBTU/HOBt or HBTU/HOAt to form activated amine -reactive esters.

[00429] Amine groups may be incorporated into oligonucleotides using a number of known, commercially available reagents at the 5’ terminus, 3’ terminus or anywhere in between.

[00430] Non-limiting examples of reagents for oligonucleotide synthesis to incorporate an amino group include:

• 5’ attachment:

• 6-(4-Monomethoxytritylamino)hexyl-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite CAS Number: 114616-27-2

• 5 ’ -Amino-Modifier TEG CE-Phosphoramidite

• 10-(O-trifluoroacetamido-N-ethyl)-triethyleneglycol-l-[(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite

• 3’ attachment:

• 3 ’ -Amino-Modifier Serinol CPG

• 3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino)propanamido)propyl-l-O-succinyl- long chain alkylamino -CPG (where CPG stands for controlled-pore glass and is the solid support)

• Amino-Modifier Serinol Phosphoramidite

• 3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino)propanamido)propyl-l-O-(2- cyanoethyl) -(N,N -diisopropyl) -phosphoramidite

[00431] Internal (base modified):

• Amino-Modifier C6 dT

• 5 ’ -Dimethoxytrityl -5 - [N -(trifluoroacetylaminohexyl) -3 -acrylimido] -2 ’ -deoxyUridine, 3 ’ - [(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. CAS Number: 178925-21-8

[00432] Solution phase conjugations may occur after oligonucleotide synthesis via reactions between non-nucleosidic nucleophilic functional groups that are attached to the oligonucleotide and electrophilic GalNAc reagents. Examples of nucleophilic groups include amines and thiols, and examples of electrophilic reagents include activated esters (e.g., N-hydroxysuccinimide, pentafluorophenyl) and maleimides.

Example 23: GalNAc ligands for hepatocyte targeting of oligonucleotides

[00433] Without limiting the disclosure to these individual methods, there are at least two general methods for attachment of multivalent N-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid or solution-phase conjugations. GalNAc ligands may be attached to solid phase resin for 3’ conjugation or at the 5’ terminus using GalNAc phosphoramidite reagents. GalNAc phosphoramidites may be coupled on solid phase as for other nucleosides in the oligonucleotide sequence at any position in the sequence. A non-limiting example of a phosphoramidite reagent for GalNAc conjugation to a 5’ end oligonucleotide is shown in Table 77.

Table 77. GalNAc Conjugation Reagent

[00434] The following includes examples of synthesis reactions used to create a GalNAc moiety:

Scheme for the preparation ofNacegal-Linker-TMSOTf

5A NAcegal-Linker-TMSOTf General procedure for preparation of Compound 2A

[00435] To a solution of Compound 1A (500 g, 4.76 mol, 476 mL) in 2-methyl-THF (2.00 L) was added CbzCI (406 g, 2.38 mol, 338 mL) in 2-methyl-THF (750 mL) dropwise at 0 °C. The mixture is stirred at 25 °C for 2 hrs under N2 atmosphere. TLC (DCM: MeOH = 20: 1, PMA) may indicate CbzCI is consumed completely and one new spot (Rf = 0.43) formed. To the reaction mixture was added HCl/EtOAc (1 N, 180 mL) and stirred for 30 mins, white solid was removed by filtration through celite, the filtrate was concentrated under vacuum to give Compound 2A (540 g, 2.26 mol, 47.5% yield) as a pale yellow oil and used into the next step without further purification. ’H NMR: 5 7.28 - 7.41 (m, 5 H), 5.55 (br s, 1 H), 5.01 - 5.22 (m, 2 H), 3.63 - 3.80 (m, 2 H), 3.46 - 3.59 (m, 4 H), 3.29 - 3.44 (m, 2 H), 2.83 - 3.02 (m, 1 H).

General procedure for preparation of Compound 4A

[00436] To a solution of Compound 3A (1.00 kg, 4.64 mol, HC1) in pyridine (5.00 L) was added acetyl acetate (4.73 kg, 46.4 mol, 4.34 L) dropwise at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. TLC (DCM: MeOH = 20: 1, PMA) indicated Compound 3A is consumed completely and two new spots (Rf = 0.35) formed. The reaction mixture was added to cold water (30.0 L) and stirred at 0 °C for 0.5 hr, white solid formed, filtered and dried to give Compound 4A (1.55 kg, 3.98 mol, 85.8% yield) as a white solid and used in the next step without further purification. ’H NMR: 5 7.90 (d, J = 9.29 Hz, 1 H), 5.64 (d, J = 8.78 Hz, 1 H), 5.26 (d, J = 3.01 Hz, 1 H), 5.06 (dd, J = 11.29, 3.26 Hz, 1 H), 4.22 (t, J = 6.15 Hz, 1 H), 3.95 - 4.16 (m, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H), 1.90 (s, 3 H), 1.78 (s, 3 H). General procedure for preparation of Compound 5A

[00437] To a solution of Compound 4A (300 g, 771 mmol) in DCE (1.50 L) was added TMSOTf (257 g, 1.16 mol, 209 mL) and stirred for 2 hrs at 60 °C, and then stirred for 1 hr at 25 °C. Compound 2A (203 g, 848 mmol) was dissolved in DCE (1.50 L) and added 4 A powder molecular sieves (150 g) stirring for 30 mins under N2 atmosphere. Then the solution of Compound 4A in DCE was added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. TLC (DCM: MeOH = 25: 1, PMA) indicated Compound 4A is consumed completely and new spot (Rf = 0.24) formed. The reaction mixture was filtered and washed with sat. NaHCOs (2.00 L), water (2.00 L) and sat. brine (2.00

L). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 2-Me-THE/heptane (5/3, v/v, 1.80 L) for 2 hrs, filtered and dried to give Compound 5A (225 g, 389 mmol, 50.3% yield, 98.4% purity) as a white solid. ’H NMR: 5 7.81 (d, J = 9.29 Hz, 1 H), 7.20 - 7.42 (m, 6 H), 5.21 (d, J = 3.26 Hz, 1 H), 4.92 - 5.05 (m, 3 H), 4.55

(d, J = 8.28 Hz, 1 H), 3.98 - 4.07 (m, 3 H), 3.82 - 3.93 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.55 - 3.62 (m, 1

H), 3.43 - 3.53 (m, 2 H), 3.37 - 3.43 (m, 2 H), 3.14 (q, J = 5.77 Hz, 2 H), 2.10 (s, 3 H), 1.99 (s, 3 H), 1.89 (s, 3 H), 1.77 (s, 3 H).

General procedure for preparation of Nacegal-Linker-Tosylate salt

[00438] To a solution of Compound 5A (200 g, 352 mmol) in THF (1.0 L) was added dry Pd/C (15.0 g, 10% purity) and TsOH (60.6 g, 352 mmol) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 3 hrs under H2 (45 psi) atmosphere. TLC (DCM: MeOH = 10: 1, PMA) indicated Compound 5A is consumed completely and one new spot (Rf = 0.04) is formed. The reaction mixture was filtered and concentrated (< 40 °C) under reduced pressure to give a residue, diluted with anhydrous DCM (500 mL, dried overnight with 4 A molecular sieves (dried at 300 °C for 12 hrs) concentrated to give a residue, and a Karl Fisher (KF) was run to check for water content. This was repeated 3 times with anhydrous DCM (500 mL) dilutions and concentration to give Nacegal-Linker-TMSOTf (205 g, 95.8% yield, TsOH salt) as a foamy white solid.

¹ H NMR: 57.91 (d, J = 9.03 Hz, 1 H), 7.53 - 7.86 (m, 2 H), 7.49 (d, J = 8.03 Hz, 2 H), 7.13 (d, J = 8.03 Hz, 2 H), 5.22 (d, J = 3.26 Hz, 1 H), 4.98 (dd, J = 11.29, 3.26 Hz, 1 H), 4.57 (d, J = 8.53 Hz, 1 H), 3.99 - 4.05 (m, 3 H), 3.87 - 3.94 (m, 1 H), 3.79 - 3.85 (m, 1 H), 3.51 - 3.62 (m, 5 H), 2.96 (br t, J = 5.14 Hz, 2 H), 2.29 (s, 3 H), 2.10 (s, 3 H), 2.00 (s, 3 H), 1.89 (s, 3 H), 1.78 (s, 3 H).

Scheme for the preparation of TRIS-PEG2-CBZ

[00439] To a solution of Compound 4B (400 g, 1.67 mol, 1.00 eq) and NaOH (10 M, 16.7 mL, 0.10 eq) in THF (2.00 L) was added Compound 4B_2 (1.07 kg, 8.36 mol, 1.20 L, 5.00 eq), the mixture was stirred at 30 °C for 2 hrs. LCMS showed the desired MS is given. Five batches of solution were combined to one batch, then the mixture was diluted with water (6.00 L), extracted with ethyl acetate (3.00 L*3), the combined organic layer was washed with brine (3.00 L), dried over Na2SC>4, filtered and concentrated under vacuum. The crude was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate=100: 1-10: 1, Rf=0.5) to give Compound 5B (2.36 kg, 6.43 mol, 76.9% yield) as light yellow oil. ’H NMR: 5 7.31-7.36 (m, 5 H), 5.38 (s, 1 H), 5.11-5.16 (m, 2 H), 3.75 (t, J=6.4 Hz), 3.54-3.62 (m, 6 H), 3.39 (d, J=5.2 Hz), 2.61 (t, J=6.0 Hz).

[00440] To a solution of Compound 5B (741 g, 2.02 mol, 1.00 eq) in DCM (2.80 L) was added TFA (1.43 kg, 12.5 mol, 928 mb, 6.22 eq), the mixture was stirred at 25 °C for 3 hrs. LCMS showed the desired MS was given. The mixture was diluted with DCM (5.00 L), washed with water (3.00 L*3), brine (2.00 L), the combined organic layer was dried over Na2SC>4, filtered and concentrated under vacuum to give Compound 2B (1800 g, crude) as light yellow oil. 'H NMR: 5 9.46 (s, 5 H), 7.27-7.34 (m, 5 H), 6.50- 6.65 (m, 1 H), 5.71 (s, 1 H), 5.10-5.15 (m, 2 H), 3.68-3.70 (m, 14 H), 3.58-3.61 (m, 6 H), 3.39 (s, 2 H), 2.55 (s, 6 H), 2.44 (s, 2 H).

1B

[00441] To a solution of Compound 2B (375 g, 999 mmol, 83.0% purity, 1.00 eq) in DCM (1.80 L) was added HATU (570 g, 1.50 mol, 1.50 eq) and DIEA (258 g, 2.00 mol, 348 m , 2.00 eq) at 0 °C, the mixture was stirred at 0 °C for 30 min, then Compound IB (606 g, 1.20 mol, 1.20 eq) was added, the mixture is stirred at 25 °C for 1 hr. LCMS showed desired MS is given. The mixture was combined to one batch, then the mixture was diluted with DCM (5.00 L), washed with 1 N HC1 aqueous solution (2.00 L*2), then the organic layer was washed with saturated Na2COs aqueous solution (2.00 L *2) and brine (2.00 L), the organic layer was dried over Na2SC>4, filtered and concentrated under vacuum to give Compound 3B (3.88 kg, crude) as yellow oil.

[00442] A solution of Compound 3B (775 g, 487 mmol, 50.3% purity, 1.00 eq) in HCl/dioxane (4 M, 2.91 L, 23.8 eq) was stirred at 25 °C for 2 hrs. LCMS showed the desired MS was given. The mixture is concentrated under vacuum to give a residue. Then the combined residue was diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M NaOH aqueous solution, and separated. The aqueous phase is extracted with DCM (3.00 L) again, then the aqueous solution was adjusted to pH=3 with 1 N HC1 aqueous solution, then extracted with DCM (5.00 L*2), the combined organic layer is washed with brine (3.00 L), dried over Na₂SC>4, fdtered and concentrated under vacuum. The crude was purified by column chromatography (SiO₂, DCM:MeOH=0: 1-12: 1, 0. 1% HOAc, R_f=0.4). The residue was diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M NaOH aqueous solution, separated, the aqueous solution is extracted with DCM (3.00 L) again, then the aqueous solution was adjusted to pH=3 with 6 N HC1 aqueous solution, extracted with DCM:MeOH=10: 1 (5.00 L*2), the combined organic layer was washed with brine (2.00 L), dried over Na₂SC>4, filtered and concentrated under vacuum to give a residue. Then the residue was diluted with MeCN (5.00 L), concentrated under vacuum, and this procedure repeated twice to remove water to give TRIS-PEG2-CBZ (1.25 kg, 1.91 mol, 78.1% yield, 95.8% purity) as light yellow oil. ’H NMR: 400 MHz, MeOD, 5 7.30-7.35 (5 H), 5.07 (s, 2 H), 3.65-3.70 (m, 16 H), 3.59 (s, 4 H), 3.45 (t, J=5.6 Hz), 2.51 (t, J=6.0 Hz), 2.43 (t, 6.4 Hz).

[00443] Scheme for the preparation of TriNGal-TRIS-Peg2-Phosph 8c

TriGNal-TRIS-Peg2-Phosph 8c

[00444] To a solution of Compound 1C (155 g, 245 mmol, 1.00 eq) in acetonitrile (1500 mL) was added TBTU (260 g, 811 mmol, 3.30 eq), DIEA (209 g, 1.62 mol, 282 mL, 6.60 eq) and Compound 2C (492 g, 811 mmol, 3.30 eq, TsOH) at 0 °C, the mixture was stirred at 15 °C for 16 hrs. LCMS showed the desired MS was given. The mixture was concentrated under vacuum to give a residue, then the mixture was diluted with DCM (2000 mL), washed with 1 N HC1 aqueous solution (700 mL * 2), then saturated NaHCOs aqueous solution (700 mL *2) and concentrated under vacuum. The crude was purified by column chromatography to give Compound 3C (304 g, 155 mmol, 63.1% yield, 96.0% purity) as a yellow solid. General procedure for preparation of Compound 4C

[00445] Two batches solution of Compound 3C (55.0 g, 29.2 mmol, 1.00 eq) in MeOH (1600 mL) was added Pd/C (6.60 g, 19.1 mmol, 10.0 % purity) and TFA (3.34 g, 29.2 mmol, 2.17 mL, 1.00 eq), the mixture was degassed under vacuum and purged with FL. The mixture was stirred under FL (15 psi) at 15 °C for 2 hours. LCMS showed the desired MS was given. The mixture was fdtered and the filtrate was concentrated under vacuum to give Compound 4C (106 g, 54.8 mmol, 93.7% yield, 96.2% purity, TFA) as a white solid.

General procedure for preparation of compound 5C

[00446] Two batches in parallel. To a solution of EDCI (28.8 g, 150 mmol, 1.00 eq) in DCM (125 mL) was added compound 4a (25.0 g, 150 mmol, 1.00 eq) dropwise at 0 °C, then the mixture was added to compound 4 (25.0 g, 150 mmol, 1.00 eq) in DCM (125 mL) at 0 °C, then the mixture was stirred at 25 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate = 3 : 1, Rf = 0.45) showed the reactant was consumed and one new spot is formed. The reaction mixture is diluted with DCM (100 mL) then washed with aq.NaHCOs (250 mL * 1) and brine (250 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether : Ethyl acetate = 100 : 1 to 3 : 1), TLC (SiCL, Petroleum ether : Ethyl acetate = 3: 1), Rf= 0.45, then concentrated under reduced pressure to give a residue. Compound 5C (57.0 g, 176 mmol, 58.4% yield, 96.9% purity) was obtained as colorless oil and confirmed ¹H NMR: EW33072-2-P1A, 400 MHz, DMSO 3 9.21 (s, 1 H), 7.07-7.09 (m, 2 H), 6.67-6.70 (m, 2 H), 3.02-3.04 (m, 2 H), 2.86-2.90 (m, 2 H) General procedure for preparation of compound 6

[00447] To a mixture of compound 3 (79.0 g, 41.0 mmol, 96.4% purity, 1.00 eq, TFA) and compound 6C (14.2 g, 43.8 mmol, 96.9% purity, 1.07 eq) in DCM (800 mL) was added TEA (16.6 g, 164 mmol, 22.8 mL, 4.00 eq) dropwise at 0 °C, the mixture was stirred at 15 °C for 16 hrs. LCMS (EW33072-12- P1B, Rt = 0.844 min) showed the desired mass was detected. The reaction mixture was diluted with DCM (400 mL) and washed with aq.NaHCOs (400 mL * 1) and brine(400 mL * 1), then the mixture was diluted with DCM (2.00 L) and washed with 0.7 M Na2COs (1000 mL * 3) and brine (800 mL * 3), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue is used to next step directly without purification. Compound 6 (80.0 g, crude) was obtained as white solid and confirmed via 'H NMR: EW33072-12-P1A, 400 MHz, MeOD 37.02 - 7.04 (m, 2 H), 6.08 - 6.70 (m, 2 H), 5.04 - 5.35 (s, 3 H), 5.07 - 5.08 (d, J= 4.00 Hz, 3 H), 4.02 - 4.64 (d, J= 8.00 Hz, 3 H), 3.01 - 4.16 (m, 16 H), 3.01 - 3.70 (m, 44 H), 2.00 - 2.83 (m, 2 H), 2.68 (m, 2 H), 2.06 - 2.47 (m, 10 H), 2.14 (s, 9 H), 2.03 (s, 9 H), 1.04 - 1.95 (d, J= 4.00 Hz, 18 H).

[00448] Two batches are synthesized in parallel. To a solution of compound 6C (40.0 g, 21.1 mmol, 1.00 eq in DCM (600 mL) was added diisopropylammonium tetrazolide (3.62 g, 21.1 mmol, 1.00 eq) and compound 7c (6.37 g, 21.1 mmol, 6.71 mL, 1.00 eq) in DCM (8.00 mL) drop-wise, the mixture was stirred at 30 °C for 1 hr, then added compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) drop-wise, the mixture was stirred at 30 °C for 30 mins, then added compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) drop-wise, the mixture was stirred at 30 °C for 1.5 hrs.

LCMS (EW33072-17-P1C1, Rt = 0.921 min) showed the desired MS+1 was detected. LCMS (EW33072- 17-P1C2, Rt = 0.919 min) showed the desired MS+1 was detected. Two batches are combined for work- up. The mixture was diluted with DCM (1.20 L), washed with saturated NaHCOs aqueous solution (1.60 L * 2), 3% DMF in H2O (1.60 L * 2), H2O (1.60 L * 3), brine (1.60 L), dried overNa2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, DCM : MeOH : TEA = 100 : 3 : 2) TLC (SiO₂, DCM: MeOH = 10: 1, R_f= 0.45), then concentrated under reduced pressure to give a residue. Compound 8C (76.0 g, 34.8 mmol, 82.5% yield, 96.0% purity) was obtained as white solid and confirmed via 'HNMR: EW33072-19-P1C, 400 MHz, MeOD 3 7.13-7.15 (d, J= 8.50 Hz, 2 H), 6.95-6.97 (dd, J=8.38, 1.13 Hz, 2 H), 5.34 (d, J =2.88 Hz, 3 H), .09 (dd, J=\ 1.26, 3.38 Hz, 3 H), 4.64 (d, J =8.50 Hz, 3 H), 3.09 - 4.20 (m, 12 H), 3.08 - 3.98 (m, 5 H), 3.06 - 3.83 (m, 20 H), 3.01 - 3.65 (m, 17 H), 3.03 - 3.50 (m, 9 H), 2.87 (t, J =1.63 Hz, 2 H), 2.76 (t, J =5.94 Hz, 2 H), 2.02 - 2.50 (m, 10 H), 2.14 (s, 9 H), 2.03 (s, 9 H), 1.04 - 1.95 (d, J =6.13 Hz, 18 H), 1.24- 1.26 (d, J =6.75 Hz, 6 H), 1.18-1.20 (d, J =6.75 Hz, 6 H).

Example 24: Modification motif 1

[00449] An example FGG siRNA includes a combination of the following modifications:

• Position 9 (from 5’ to 3’) of the sense strand is 2’F.

• If position 9 is a pyrimidine then all purines in the Sense Strand are 2’OMe, and 1-5 pyrimidines between positions 5 and 11 are 2’F provided that there are never three 2’F modifications in a row.

• If position 9 is a purine then all pyrimidines in the Sense Strand are 2’OMe, and 1-5 purines between positions 5 and 11 are 2’F provided that there are never three 2’F modifications in a row.

• Antisense strand odd-numbered positions are 2’OMe and even-numbered positions are a mixture of 2’F, 2’OMe and 2’deoxy.

Example 25: Modification motif 2

[00450] An example FGG siRNA includes a combination of the following modifications:

• Position 9 (from 5’ to 3’) of the sense strand is 2’deoxy.

• Sense strand positions 5, 7 and 8 are 2’F.

• All pyrimidines in positions 10-21 are 2’OMe, and purines are a mixture of 2’OMe and 2’F. Alternatively, all purines in positions 10-21 are 2’OMe and all pyrimidines in positions 10-21 are a mixture of 2’OMe and 2’F.

Example 26: Inhibition of FGG in an AAV-Mediated Mouse Model of Hyperfibrinogenemia Using Modified FGG siRNAs.

[00451] In this experiment, an AAV -mediated mouse model of hyperfibrinogenemia is used to evaluate the effect of siRNA inhibition of FGG. Eight- to ten-week-old female mice (C57BL/6J) will be injected with three recombinant adeno-associated virus 8 (AAV8) vectors by the retroorbital route on Day -14. Each recombinant AAV8 encodes one of three distinct polypeptides, designated Aa, B|3 and y from which fibrinogen is composed and contains the open reading frame and a portion of the 5’ and 3’UTRs of the mouse FGA, FGB, or FGG sequence under the control of the thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-m-FGA, AAV8-TBG-m-FGB and AAV8- TBG-m-FGG). On Day -14 (prior to infection), Day 0 (prior to dosing), and at time points specified below, blood will be collected into tubes with 0.2mL sodium citrate for collection of plasma.

Additionally, on Day 0 and Day 7, mice will be given a subcutaneous injection of a single dose of a GalNAc -conjugated siRNA, non-targeting siRNA or PBS as vehicle control.

[00452] Briefly, C57B1/6J mice will be divided into five groups: Group 1 - a group infected with AAV8 vectors and receiving non -targeting control siRNA, Group 2 - a group infected with AAV8 vectors and receiving vehicle, Group 3 - a group infected with AAV8 vectors and receiving FGG siRNA, Group 4 - a group treated with vehicle, and Group 5 - a group treated with FGG siRNA. Each group contains 8 female mice.

[00453] On Study Days 7 and 14, four mice from each group will be sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). A liver sample will be collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples will be processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate will be purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample will be assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice using the delta-delta Ct method. Plasma will also be collected, and plasma fibrinogen levels will be measured using the Clauss method or by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT).

[00454] A decrease in FGG mRNA expression in the liver tissue from mice dosed with the FGG siRNA is expected compared to FGG mRNA levels in the liver tissue from mice dosed with the nontargeting controls or vehicle. Additionally, AAV-8 infected mice that receive control treatment will have increased FGG mRNA expression in liver tissue compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. Similarly, measurement of plasma fibrinogen levels is expected to show a decrease in fibrinogen in the mice dosed with the FGG siRNA compared to fibrinogen from the plasma of mice dosed with non -targeting control. AAV-8 infected mice that receive control treatment will have increased plasma fibrinogen compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. Results obtained on Day 7 and 14 will provide information on steady state levels of fibrinogen from AAV8 infection. Example 27: Assessment of Hearing Function Using Auditory Brainstem Response Threshold After Inhibition of FGG in an AAV-Mediated Mouse Model of Hyperfibrinogenemia Using Modified FGG siRNAs.

[00455] Using an AAV-mediated mouse model of hyperfibrinogenemia, this study will investigate the effect of elevated serum levels of fibrinogen on hearing function assessed by Auditory Brainstem Response (ABR) Thresholds. ABR is an electrophysiological brain response that plays a series of sounds to the subject at different frequencies and intensities. By measuring the synchronized electrical responses of the cochlea, auditory nerve, and brainstem, the test will measure hearing loss resulting from hyperfibrinogenemia.

[00456] Eight- to ten-week-old female mice (C57BL/6J) will be injected with three recombinant adeno-associated virus 8 (AAV8) vectors by the retroorbital route on Day -14. Each recombinant AAV8 encodes one of three distinct polypeptides, designated Aa, B|3 and y from which fibrinogen is composed and contains the open reading frame and a portion of the 5’ and 3’UTRs of the mouse FGA, FGB, or FGG sequence under the control of the thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-m-FGA, AAV8-TBG-m-FGB and AAV8-TBG-m-FGG). On Day -14 (prior to infection), Day 0 (prior to dosing), and at time points specified below, blood will be collected into tubes with 0.2mL sodium citrate for collection of plasma. Additionally, on Day 0 and Day 7, mice will be given a subcutaneous injection of a single dose of a GalNAc -conjugated FGG siRNA, or a GalNAc -conjugated non-targeting siRNA, or PBS as vehicle control.

[00457] Briefly, C57B1/6J mice will be divided into five groups: Group 1 - a group infected with AAV8 vectors followed by treatment with non -targeting control siRNA, Group 2 - a group infected with AAV8 vectors followed by treatment with vehicle, Group 3 - a group infected with AAV8 vectors followed by treatment with FGG siRNA, Group 4 - a group treated with vehicle, and Group 5 - a group treated with FGG siRNA. Each group contains 5 female mice.

[00458] On Days -14 (prior to infection), Day 7, and Day 14, mice will be anesthetized with ketamine/xylazine. ABR thresholds will be obtained by presenting tone bursts at varying frequencies at increasing sound intensities. Electrodes will be placed subdermally, one behind the right pinna of the sound exposed ear and the other along the vertex. The unexposed ear will be obstructed with a cotton plug. Evoked potentials will be averaged over 300 repetitions. These potentials will be amplified, filtered (100-3,000 Hz bandpass), digitized and stored on a computer hard drive. Thresholds, the smallest sound amplitude that evoked a visible ABR, will be determined by visually examining the averaged ABR waveforms in response to every sound frequency presented at different sound levels.

[00459] After final hearing threshold assessments, mice will be sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). A liver sample will be collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples will be processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate will be purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample will be assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice using the delta-delta Ct method. Plasma will also be collected, and plasma fibrinogen levels will be measured using the Clauss method or by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT).

[00460] A decrease in FGG mRNA expression in the liver tissue from mice dosed with the FGG siRNA is expected compared to FGG mRNA levels in the liver tissue from mice dosed with the nontargeting controls or vehicle. Additionally, AAV-8 infected mice that receive control treatment will have increased FGG mRNA expression in liver tissue compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. Similarly, measurement of plasma fibrinogen levels is expected to show a decrease in fibrinogen in the mice dosed with the FGG siRNA compared to fibrinogen from the plasma of mice dosed with non -targeting control. AAV-8 infected mice that receive control treatment will have increased plasma fibrinogen compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. The increased levels of plasma fibrinogen resulting from AAV-8 infection are expected to result in increased hearing thresholds. The attenuation of fibrinogen levels in mice treated with FGG siRNA are expected to maintain hearing thresholds similar to baseline.

Example 28: Assessment of Hearing Function Using Prepulse Inhibition of the Acoustic Startle Reflex After Inhibition of FGG in an AAV-Mediated Mouse Model of Hyperfibrinogenemia Using Modified FGG siRNAs.

[00461] Using an AAV-mediated mouse model of hyperfibrinogenemia, this study will investigate the effect of elevated serum levels of fibrinogen on hearing function assessed by behavioral testing (Prepulse inhibition (PPI) of the acoustic startle reflex). Briefly, an auditory stimulus (Prepulse) is presented prior to the startle stimulus (pulse) and the degree of startle is quantified. The behavioral audiogram is conducted by altering the pitch and/or intensity of this prepulse stimulus to assess the ability of inhibition on the actual startle reflex and allows for analysis of hearing loss resulting from hyperfibrinogenemia.

[00462] Eight- to ten-week-old female mice (C57BL/6J) will be injected with three recombinant adeno-associated virus 8 (AAV8) vectors by the retroorbital route on Day -14. Each recombinant AAV8 encodes one of three distinct polypeptides, designated Aa, B|3 and y from which fibrinogen is composed and contains the open reading frame and a portion of the 5’ and 3’UTRs of the mouse FGA, FGB, or FGG sequence under the control of the thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-m-FGA, AAV8-TBG-m-FGB and AAV8-TBG-m-FGG). On Day -14 (prior to infection), Day 0 (prior to dosing), and at time points specified below, blood will be collected into tubes with 0.2mL sodium citrate for collection of plasma. Additionally, on Day 0 and Day 7, mice will be given a subcutaneous injection of a single dose of a GalNAc -conjugated FGG siRNA, or a GalNAc -conjugated non-targeting siRNA, or PBS as vehicle control. [00463] Briefly, C57B1/6J mice will be divided into five groups: Group 1 - a group infected with AAV8 vectors followed by treatment with non -targeting control siRNA, Group 2 - a group infected with AAV8 vectors followed by treatment with vehicle, Group 3 - a group infected with AAV8 vectors followed by treatment with FGG siRNA, Group 4 - a group treated with vehicle, and Group 5 - a group treated with FGG siRNA. Each group contains 5 female mice.

[00464] On Days -14 (prior to infection), Day 7, and Day 14, mice will be assessed by reflex-based behavioral testing to determine hearing thresholds. A burst of white noise will be used as the acoustic startle stimulus. Typical durations are 20 ms for prepulse and 40 ms for pulse. Background noise will be 30-40 dB and prepulse will be set 3-12 dB louder than background. Startle response is measured using automated startle chambers with detectors recording whole-body reaction.

[00465] After final hearing threshold assessments, mice will be sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). A liver sample will be collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples will be processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate will be purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample will be assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice using the delta-delta Ct method. Plasma will also be collected, and plasma fibrinogen levels will be measured using the Clauss method or by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT).

[00466] A decrease in FGG mRNA expression in the liver tissue from mice dosed with the FGG siRNA is expected compared to FGG mRNA levels in the liver tissue from mice dosed with the nontargeting controls or vehicle. Additionally, AAV-8 infected mice that receive control treatment will have increased FGG mRNA expression in liver tissue compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. Similarly, measurement of plasma fibrinogen levels is expected to show a decrease in fibrinogen in the mice dosed with the FGG siRNA compared to fibrinogen from the plasma of mice dosed with non -targeting control. AAV-8 infected mice that receive control treatment will have increased plasma fibrinogen compared to non-infected control groups as well as AAV-8 infected mice treated with FGG siRNA. The increased levels of plasma fibrinogen resulting from AAV-8 infection are expected to result in increased hearing thresholds. The attenuation of fibrinogen levels in mice treated with FGG siRNA are expected to maintain hearing thresholds similar to baseline. Example 29: Assessment of Hearing Function After Inhibition of FGG in an LPS-induced Hyperfibrinogenemia Mouse Model Using Modified FGG siRNAs.

[00467] Using a Lipopolysaccharide (LPS) induced mouse model of hyperfibrinogenemia, this study will investigate the effect of elevated serum levels of fibrinogen on hearing function assessed by Auditory Brainstem Response (ABR) Thresholds.

[00468] Briefly, eight- to ten-week-old female C57B1/6J mice will be divided into four groups: Group 1 - a group pretreated with a GalNAc -conjugated non-targeting control siRNA followed by albumin (control) injection, Group 2 - a group pretreated with a GalNAc -conjugated non-targeting siRNA followed by LPS injection, Group 3 - group pretreated with a GalNAc -conjugated FGG siRNA followed by albumin (control) injection, and Group 4 - group pretreated with a GalNAc -conjugated FGG siRNA followed by LPS injection. Each group contains 5 female mice.

[00469] On Day 0, mice will be injected with FGG siRNA or non -targeting siRNA by subcutaneous injection. On Day 7, mice will receive an intraperitoneal (i.p.) injection with lipopolysaccharide or equimolar amount of albumin. Mice will be euthanized 24 hours after LPS injection following auditory testing, and blood and livers collected for analysis.

[00470] ABR thresholds will be obtained on Day -3 (baseline) and Day 8 (post LPS injection). Briefly, mice will be anesthetized with ketamine/xylazine and ABR thresholds will be obtained by presenting tone bursts at varying frequencies at increasing sound intensities. Electrodes will be placed subdermally, one behind the right pinna of the sound exposed ear and the other along the vertex. The unexposed ear will be obstructed with a cotton plug. Evoked potentials will be averaged over 300 repetitions. These potentials will be amplified, filtered (100-3,000 Hz bandpass), digitized and stored on a computer hard drive. Thresholds, the smallest sound amplitude that evoked a visible ABR, will be determined by visually examining the averaged ABR waveforms in response to every sound frequency presented at different sound levels.

[00471] After final hearing threshold assessments, mice will be sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). A liver sample will be collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples will be processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate will be purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample will be assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice using the delta-delta Ct method. Plasma will also be collected, and plasma fibrinogen levels will be measured using the Clauss method or by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT). [00472] Mice injected with LPS are expected to develop increased levels of plasma fibrinogen which will paralleled by increased hearing thresholds. Mice pretreated with FGG siRNA will attenuate fibrinogen levels following acute inflammatory challenge by LPS compared to non-targeting siRNA and vehicle controls and are expected to maintain hearing thresholds similar to baseline. Additionally, hepatic FGG mRNA levels will be decreased in FGG siRNA treated mice compared with non-targeting siRNA and vehicle treated mice after LPS injection.

Example 30: Screening siRNAs with alternative modification patterns of ETD01841 and ETD01926 in mice

[00473] The base sequences of ETD01841 and ETD01926 were synthesized to generate siRNAs (ETD02341-ETD02344 and ETD02345-ETD02348, respectively) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 78, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 79.

[00474] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single lOOpg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to mice receiving PBS. Results are shown in Table 80. Injection of mice with alternatively modified versions of ETD01841 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01841. Injection of mice with alternatively modified versions of ETD01926, namely ETD02345 and ETD02348, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01926.

[00475] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 81. Injection of mice with alternatively modified versions of ETD01841 had lower relative levels of mouse FGG mRNA than mice receiving ETDO 1841. None of the alternatively modified versions of ETDO 1926 had higher activity than ETDO 1926 in terms of lower mouse liver FGG mRNA levels.

Table 78. Example siRNA Sequences

Table 79. Example siRNA BASE Sequences

Table 80. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 81. Relative FGG mRNA Levels in Livers of Mice

Example 31. Screening siRNAs with alternative modification patterns of the antisense strand of

ETD01841 ETD02341 in mice

[00476] The sense strand of ETD01841 was duplexed with alternatively modified antisense strands to generate siRNAs ETD02480-ETD02482. The sense strand of ETD02341 was duplexed with alternatively modified antisense strands to generate siRNAs and ETD02577, ETD02578) These were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 82, where “Nf ’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 83.

[00477] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. ETD01831 and ETD02341 were included as positive siRNA controls for comparison. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 84. Injection of mice with an alternatively modified version of ETD01841, namely ETD02481, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01841. Injection of mice with alternatively modified versions of ETD02341, namely ETD02577 and ETD02578, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02341.

[00478] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 85. None of the mice injected with alternatively modified versions of ETD01841 had lower relative levels of mouse liver FGG mRNA. None of the mice injected with alternatively modified versions of ETD02341 had lower relative levels of mouse liver FGG mRNA.

Table 82. Example siRNA Sequences

Table 83. Example siRNA BASE Sequences

Table 84. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 85. Relative FGG mRNA Levels in Livers of Mice

Example 32: Modification motif 3

[00479] An example siRNA includes a combination of the following modifications:

• All positions of the sense strand are 2’F, 2’0-methoxyethyl, or 2’-O-methyl

• All antisense strands are 2’F or 2’-O-methyl

Example 33: Modification motif 4

[00480] An example siRNA includes a combination of the following modifications:

• Positions 6-9 of the sense strand is 2’F.

• Positions 4 or 5 of the sense strand is 2’-O-methoxyethyl

• Positions 16-20 of the sense strand are 2’-O-methyl

• All remaining positions of the sense strand are 2’F, 2’-O-methoxyethyl, or 2’-O-methyl

• All antisense strands are 2’F or 2’-O-methyl

Example 34: Screening of siRNAs ETD02483-ETD02502 targeting human FGG mRNA in mice transfected with AAV8-TBG-h-FGG

[00481] The activities of siRNAs, namely ETD02483-ETD02502, were assessed in mice transiently expressing human FGG. ETD01926 was used as a positive control siRNA. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 86, where Nf is a 2’-fluoro-modified nucleoside, n is a 2’-O-methyl modified nucleoside, dN is a 2’-deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 87. ETD02493-ETD02502 were tested in Part 1 of the study and ETD02483-ETD02492 were tested in Part 2. [00482] Six-to-eight week old female mice (C57B1/6) were injected with 5 pL of a recombinant adeno-associated virus 8 (AAV8) vector (2.4 x 10E13 genome copies/mL) by the retroorbital route on Day -18 (Part 1) or Day -17 (Part 2). The recombinant AAV8 contains the open reading frame and a portion of the 5’ and 3’UTRs of the human FGG sequence (ENST00000404648) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8- TBG-h-FGG). On Day 0, infected mice (n=5) were given a subcutaneous injection of a single lOOug dose of a GalNAc -conjugated siRNA or PBS as vehicle control.

[00483] On Day 0 (prior to dosing), Day 4 and Day 10 in Part 1, and on Day 0 and Day 10 in Part 2, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results for Part 1 are shown in Table 88, and those for Part 2 in Table 89. Mice injected with ETD02490, ETD02491 or ETD02492 had the greatest reduction in mean plasma fibrinogen relative to mice receiving PBS.

[00484] Mice were euthanized on Day 10 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell® RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human FGG (ThermoFisher, assay# Hs00241038_ml), or mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g 1 ), and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results for Part 1 are shown in Table 90, and those for Part 2 in Table 91. Of the siRNAs in this screening set, mice injected with ETD02483, ETD02490, ETD02491 or ETD02492 had the highest level of human and mouse FGG mRNA knockdown in the liver.

Table 86. Example siRNA Sequences

Table 87. Example siRNA BASE Sequences

Table 88. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG - Part 1

Table 89. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG - Part 2

Table 90. Relative FGG mRNA Levels in Livers of Mice Transfected with AAV8-TGB-h-FGG - Part 1

Table 91. Relative FGG mRNA Levels in Livers of Mice Transfected with AAV8-TGB-h-FGG - Part 2

Example 35: Screening siRNAs with alternative modification patterns of ETD02490 in mice

[00485] The base sequence of ETD02490 was synthesized to generate siRNAs (ETD02635- ETD02640) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 92, where Nf is a 2’-fluoro- modified nucleoside, n is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 93.

[00486] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60ug dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 94. Injection of mice with the alternatively modified versions of ETD02490 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02490. Of the alternatively modified versions, ETD02638 had the greatest activity.

[00487] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell® RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g l ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 95. Injection of mice with the alternatively modified versions of ETD02490 resulted in lower relative levels of mouse liver FGG mRNA than mice receiving ETD02490. Of the alternatively modified versions of ETD02490, ETD02638 had the greatest activity.

Table 92. Example siRNA Sequences

Table 93. Example siRNA BASE Sequences

Table 94. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 95. Relative FGG mRNA Levels in Livers of Mice

Example 36: Screening siRNAs with alternative modification patterns of ETD02491 in mice

[00488] The base sequence of ETD02491 was synthesized to generate siRNAs (ETD02641- ETD02647) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 96, where Nf is a 2’-fluoro- modified nucleoside, n is a 2’-O-methyl modified nucleoside, dN is a 2’ -deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 97. [00489] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60ug dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 98. Injection of mice with several of the alternatively modified versions of ETD02491 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02491. Of the alternatively modified versions, ETD02646 had the greatest activity.

[00490] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 99. Injection of mice with alternatively modified versions of ETD02491 resulted in lower relative levels of mouse liver FGG mRNA than mice receiving ETD02491. Of the alternatively modified versions of ETD02491, ETD02646 had the greatest activity.

Table 96. Example siRNA Sequences

Table 97. Example siRNA BASE Sequences

Table 98. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 99. Relative FGG mRNA Levels in Livers of Mice

Example 37: Screening siRNAs with alternative modification patterns of ETD02492 in mice

[00491] The base sequence of ETD02492 was synthesized to generate siRNAs (ETD02648- ETD02655) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 100, where “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “d” is a 2’ -deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 101.

[00492] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60ug dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 102. Injection of mice with several of the alternatively modified versions of ETD02492 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02492. Of the alternatively modified versions, ETD02650 and ETD02652 had the greatest activities.

[00493] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 103. Mice injected with alternatively modified versions of ETD02492 had lower relative levels of mouse liver FGG mRNA than mice receiving ETD02492. Of the alternatively modified versions of ETD02492, ETD02652 had the greatest activity.

Table 100. Example siRNA Sequences

Table 101. Example siRNA BASE Sequences

Table 102. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 103. Relative FGG mRNA Levels in Livers of Mice

Example 38: Screening siRNAs with alternative modification patterns of ETD02483 in mice [00494] The base sequence of ETD02483 was synthesized to generate siRNAs (ETD02662- ETD02665) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 104, where “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “run” is a 2’-O-methoxyethyl modified nucleoside, “d” is a 2’ -deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 105.

[00495] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 50ug dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 106. Injection of mice with the alternatively modified versions of ETD02483 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02483. Of the alternatively modified versions, ETD02663 and ETD02665 had the greatest activities.

[00496] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 107. Mice injected with alternatively modified versions of ETD02483 had lower relative levels of mouse liver FGG mRNA than mice receiving ETD02483. Of the alternatively modified versions of ETD02483, ETD02663 and ETD02665 had the greatest activities.

Table 104. Example siRNA Sequences

Table 105. Example siRNA BASE Sequences

Table 106. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 107. Relative FGG mRNA Levels in Livers of Mice

Example 39: Screening siRNAs with alternative modification patterns of ETD02491 and ETD02492 in mice

[00497] The base sequences of ETD02491 and ETD02492 were synthesized to generate siRNAs (ETD02668-ETD02671 and ETD02672-ETD02675, respectively) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 108, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “d” is a 2’-deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 109.

[00498] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 50ug dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 110. Injection of mice with alternatively modified versions of ETD02491, namely ETD02668 and ETD02669, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02491. None of the alternatively modified versions of ETD02492 had higher activity than ETD02492 in terms of lower plasma fibrinogen levels.

[00499] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 111. Injection of mice with alternatively modified versions of ETD02491, namely ETD02668, ETD02669 and ETD02671, had lower relative levels of mouse FGG mRNA than mice receiving ETD02491. None of the alternatively modified versions of ETD02492 had higher activity than ETD02492 in terms of lower mouse liver FGG mRNA levels.

Table 108. Example siRNA Sequences

Table 109. Example siRNA Base Sequences

Table 110. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 111. Relative FGG mRNA Levels in Livers of Mice

Example 40: Screening siRNAs with alternative modification patterns of the antisense strand of ETD02483 in mice.

[00500] The sense strand of ETD02483 was duplexed with alternatively modified antisense strands to generate siRNAs ETD02629-ETD02634. These were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 112, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 113. [00501] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60 pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. ETD02483 was included as a positive siRNA control for comparison. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 114. Injection of mice with alternatively modified versions of ETD02483, namely ETD02631 and ETD02634, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02483.

[00502] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell® RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 115. Of the alternatively modified versions of ETD02483, ETD02431 and ETD02634 had the lowest relative levels of mouse liver FGG mRNA.

Table 112. Example siRNA Sequences

Table 113. Example siRNA BASE Sequences

Table 114. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 115. Relative FGG mRNA Levels in Livers of Mice

Example 41: Comparing the activity of siRNAs targeting human FGG mRNA in mice transfected with AAV8-TBG-h-FGG

[00503] The activities of species cross-reactive siRNAs, namely ETD01926, ETD02341, ETD02647, ETD02638, ETD02646, and ETD02652 were assessed in mice transiently expressing human FGG. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 116, where “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “d” is a 2’ -deoxynucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 117. [00504] Six to eight week old female mice (C57B1/6) were injected with 5 pL of a recombinant adeno-associated virus 8 (AAV8) vector (1.6 x 10E13 genome copies/mL) by the retroorbital route on Day -14. The recombinant AAV8 contains the open reading frame and a portion of the 5’ and 3’UTRs of the human FGG sequence (ENST00000404648) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-FGG). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 60 pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 0 (prior to dosing) and Day 10 blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 118. Mice injected with ETD02341, ETD02638 or ETD02652 had the greatest reduction in mean plasma fibrinogen relative to mice receiving PBS. Mice were euthanized on Day 10 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human FGG (ThermoFisher, assay# Hs00241038_ml), or mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results for Part 1 are shown in Table 119. Of the siRNAs in the screening set, mice injected with ETD02652 had the highest level of human FGG mRNA knockdown in the liver and ETD02341, ETD02646 and ETD02652 had the highest levels of mouse FGG mRNA knockdown in the liver.

Table 116. Example siRNA Sequences

Table 117. Example siRNA BASE Sequences

Table 118. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 119. Relative FGG mRNA Levels in Livers of Mice Transfected with AAV8-TGB-h-FGG

Example 42: Screening blunt-ended versions of ETD01926 and ETD02341 siRNAs in mice [00505] Duplexes were prepared in which the antisense strand was synthesized without the 2 nucleotide overhang at the 3’ end, thus resulting in a duplex that was blunt-ended at the 3’ end of the antisense strand. In addition, additional duplexes were prepared in which the sense strand was synthesized without the 5’ terminal nucleotide present in the parental strand, and the antisense strand was synthesized as an 18mer such that the 3 ’ end of the antisense strand made a blunt end with the 5 ’ nucleotide of the sense strand. These were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 120, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA are shown in Table 121.

[00506] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. ETD01926 and ETD02341 were included as positive siRNA controls for comparison.

[00507] On Day 0 (prior to dosing), Day 7, Day 14, Day 21, and Day 28, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 122. Injection of mice with a blunt-ended version of ETD01926, namely ETD02680, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01926 at most timepoints. Of all the blunt-ended versions of ETD02341, mice injected with ETD02684 resulted in the lowest relative levels of mean plasma fibrinogen.

[00508] Mice were euthanized on Day 28 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell® RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 123. None of the mice injected with blunt-ended versions of ETD01926 had lower relative levels of mouse liver FGG mRNA on Day 28. None of the mice injected with the blunt- ended variant of ETD02341 had lower relative levels of mouse liver FGG mRNA on Day 28.

Table 120. Example siRNA Sequences

Table 121. Example siRNA BASE Sequences

Table 122. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 123. Relative FGG mRNA Levels in Livers of Mice

Example 43: Determining the activity and safety of multiple doses of siRNAs targeting FGG in nonhuman primates

[00509] Five groups (n=4/group) of 4-7 year old male cynomolgus monkeys (Zhaoqing Chuangyao Biotechnology Co., Ltd and Guangzhou Xianngguan Biotechnology Co., Ltd) were utilized for this study. [00510] The siRNAs used in this Example are included in Table 124, where “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 125. On Study Day 0, Group 1 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with PBS vehicle control, Group 2 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 5mg/kg ETD01841 at a concentration of 25mg/mL, Group 3 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01841 at a concentration of lOmg/mL, Group 4 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 5mg/kg ETD01926 at a concentration of 25mg/mL, Group 5 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01926 at a concentration of lOmg/mL. On Study Days 30, 60, 90, 120 and 150, Group 1 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with PBS vehicle control, Group 2 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01841 at a concentration of lOmg/mL, Group 3 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01841 at a concentration of lOmg/mL, Group 4 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01926 at a concentration of lOmg/mL, Group 5 cynomolgus monkeys were injected subcutaneously (0.2mL/kg) with 2mg/kg ETD01926 at a concentration of lOmg/mL. All animals had no abnormal clinical symptoms and well tolerated with multiple subcutaneous doses at 5 or 2 mg/kg of ETD01841 and ETD01926.

Table 124. Example siRNA Sequences

Table 125. Example siRNA BASE Sequences

[00511] On Study Days -8, -2, 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, 98, 105, 112, 119, 126, 133, 140, 147, 154, 161, and Day 168 body weights were recorded.

[00512] On Study Days -8, 28, 49 and Day 71 the animals were anesthetized with Zoletil (1.5 - 5.0 mg/kg, i.m.) and xylazine (0.5 - 2.0 mg/kg, i.m.) and 3-4mg liver biopsy was collected. The biopsy was placed in 10 v/v RNAlater in 20 seconds and stored for 24 hrs at 4°C, the RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020) was then removed and the liver tissue was stored in freezer until they were shipped to Empirico. There were no abnormal clinical observations for all animals after liver biopsy collection on Day -8, 28, 29, or Day 71. The liver samples were processed in homogenization buffer (Maxwell RSC simply RNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative level of FGG mRNA in each Study Day 28 liver biopsy sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for cynomolgus FGG (ThermoFisher, assay# Mf02793821_ml) and the cynomolgus housekeeping genes GUSB, ARFGAP2, ARL1, B2M, GAPDH, and YWHAZ (ThermoFisher, assay# Mf04392669_ml, Mf01058488_gl, Mf02795431ml, Mf07269219_sl, Mf04392546_gl, Mf02793821_ml), and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean value of the Study Day -2 using the delta-delta Ct method.

[00513] On Study Days -2,-8, 7, 14, 21, 35, 42, 56, 63, 70, 77, 84, 91, 98, and Day 105 blood was collected into tubes with 0.2mL sodium citrate for collection of plasma. Plasma samples were analyzed for PT and APTT and the remaining plasma samples were stored in a freezer. Plasma samples were then transferred to IDEXX Laboratories and plasma fibrinogen levels were measured by the Clauss method (IDEXX Laboratories, Test# 6308).

[00514] On Study Days -8, 0, 7, 21, 35, 49,63, 77, 91, 105, 119, 133, 147, and Day 161 blood was collected into tubes with no anti-coagulant serum collected. Clinical chemistry parameters including alanine L transferase (ALT), aspartate aminostransferase (AST), alkaline phosphatase (ALP), direct bilirubin (DBIL), total bilirubin (TBIL), glucose (GLU), urea (UREA), creatinine (CREA), triglycerides (TG), cholesterol (CHOL), total protein (TP) and gamma glutamyl transferase (GGT) were analyzed. [00515] On Study Days -8, 0, 7, 21, 35, 49,63, 77, 91, 105, 119, 133, 147, and Day 161 blood was collected into tubes with no EDTA-K2 as an anti -coagulant. Hematology parameters containing white blood cell (WBC), neutrophils (NEUT#), lymphocyte (LYM#), monocytes (MONO#), eosinophils (EOS#), basophils (BASO#), neutrophil percentage (NEUT%), lymphocyte percentage (LYM%), monocyte percentage M0N0%, eosinophil percentage EOS%, basophil percentage BASO%, red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width standard deviation (RDW-SD), red blood cell distribution width coefficient of variation (RDW- CV), platelet count (PLT), reticulocyte count (RET), and reticulocyte percentage (RET%) were analyzed. [00516] The weights of the animals are shown in Table 126. Animals treated with ETD01841 with an initial dose of 5 mg/kg, followed by subsequent doses of 2 mg/kg (5mg/2mg/kg, Group 2), or treated with 2 mg/kg for all doses (2mg/kg, Group 3), for six monthly doses showed normal gain in relative bodyweights over the treatment period which indicate all the siRNA were generally well tolerated. Animals treated with ETD01926 with an initial dose of 5 mg/kg, followed by subsequent doses of 2 mg/kg (5mg/2mg/kg, Group 4), or treated with 2 mg/kg for all doses (2mg/kg, Group 5), for six monthly doses showed normal gain in relative bodyweights over the treatment period which indicate all the siRNA were generally well tolerated. The results of the liver mRNA analysis are shown in Table 127. Group 2 and Group 3 animals treated with ETD01841 or Group 4 and Group 5 animals treated with ETD01926 for six monthly doses showed decreased liver FGG mRNA levels on Study Day 28, 49, and Day 71 compared to liver biopsies obtained from the same animals on Study Day -2. The results of the plasma coagulation parameters are shown in Tables 128-129. Group 2 and Group 3 animals treated with ETD01841 or Group 4 and Group 5 animals treated with ETD01926 for six monthly doses showed slightly elevated PT times starting on Day 14 with no change in APTT times though Study Day 168 when compared to Study Day -8 and Study Day -2, prior to treatment. The results of the plasma fibrinogen are shown in Table 130. Group

2 and Group 3 animals treated with ETD01841 or Group 4 and Group 5 animals treated with ETD01926 for six monthly doses showed a decrease in plasma fibrinogen starting on Study Day 7 though Study Day 105 when compared to Study Day -8 and Study Day -2, prior to treatment. The results of the clinical chemistry parameters are shown in Tables 131-149. Group 2 and Group 3 animals treated with ETD01841 or Group 4 and Group 5 animals treated with ETD01926 for six monthly doses showed no significant change in ALT, AST, ALP, DBIL, TBIL, GLU, UREA, CREA, TG, CHOL, TP and GGT starting on Study Day 7 though Study Day 161 when compared to Study Day -8 and Study Day -2, prior to treatment. The results of the hematology parameters are shown in Tables 150-164. Group 2 and Group

3 animals treated with ETD01841 or Group 4 and Group 5 animals treated with ETD01926 for six monthly doses showed no significant change in WBC, NEUT#, LYM#, MONO#, EOS#, BASO#, NEUT%, LYM%, M0N0%, EOS%, BASO%, RBC, HGB, HCT, MCV, MCH, MCHC, RDW-SD, RDW-CV, PLT, RET, and RET% starting on Study Day 7 though Study Day 161 when compared to Study Day -8 and Study Day -2, prior to treatment.

Table 126. Body Weights in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 127. Day 28, 49, 71 FGG mRNA liver levels in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 128. Prothrombin time in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 129. Activated Partial Thromboplastin time in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 130. Plasma fibrinogen levels in Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 131. Clinical Chemistry ALT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 132. Clinical Chemistry AST results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 133. Clinical Chemistry ALP results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 134. Clinical Chemistry DBIL results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 135. Clinical Chemistry TBIL results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 136. Clinical Chemistry GLU results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 137. Clinical Chemistry UREA results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 138. Clinical Chemistry CREA results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 139. Clinical Chemistry TG results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 140. Clinical Chemistry CHOL results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 141. Clinical Chemistry TP results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 142. Clinical Chemistry GGT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 143. Clinical Chemistry WBC results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 144. Clinical Chemistry NEUT# results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 145. Clinical Chemistry LYM# results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 146. Clinical Chemistry MONO# results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 147. Clinical Chemistry EOS# results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 148. Clinical Chemistry BASO# results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 149. Clinical Chemistry NEUT% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 150. Clinical Chemistry LYM% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 151. Clinical Chemistry MONO% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 152. Clinical Chemistry EOS% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 153. Clinical Chemistry BASO% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 154. Clinical Chemistry RBC results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 155. Clinical Chemistry HGB results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 156. Clinical Chemistry HCT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 157. Clinical Chemistry MCV results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 158. Clinical Chemistry MCH results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 159. Clinical Chemistry MCHC results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 160. Clinical Chemistry RDW-SD results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 161. Clinical Chemistry RDW-CV results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 162. Clinical Chemistry PLT results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 163. Clinical Chemistry RET results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Table 164. Clinical Chemistry RET% results of Cynomolgus Monkeys treated with siRNAs targeting FGG

Example 44: Screening siRNAs with alternative modification patterns of ETD01841 and ETD01926 in mice

[00517] The base sequences of ETD01841 and ETD01926 were synthesized to generate siRNAs (ETD02341-ETD02344 and ETD02345-ETD02348, respectively) with alternative modification patterns and then these were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 165, where “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 166.

[00518] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single lOOpg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. On Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to mice receiving PBS. Results are shown in Table 167. Injection of mice with alternatively modified versions of ETD01841 resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01841. Injection of mice with alternatively modified versions of ETD01926, namely ETD02345 and ETD02348, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01926.

[00519] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell® RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell® RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript™ cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 168. Injection of mice with alternatively modified versions of ETD01841 had lower relative levels of mouse FGG mRNA than mice receiving ETD01841. None of the alternatively modified versions of ETD01926 had higher activity than ETD01926 in terms of lower mouse liver FGG mRNA levels. Table 165. Example siRNA Sequences

Table 166. Example siRNA BASE Sequences

Table 167. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Example 45. Screening siRNAs with alternative modification patterns of the antisense strand of ETD01841 ETD02341 in mice

[00520] The sense strand of ETD01841 was duplexed with alternatively modified antisense strands to generate siRNAs ETD02480-ETD02482. The sense strand of ETD02341 was duplexed with alternatively modified antisense strands to generate siRNAs and ETD02577, ETD02578) These were tested for activity in mice. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNAs used in this Example are included in Table 169, where “Nf ’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA, with and without the 3’ UU extension, are shown in Table 170.

[00521] Six to eight week old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60pg dose of a GalNAc -conjugated siRNA or PBS as vehicle control. ETD01831 and ETD02341 were included as positive siRNA controls for comparison. On Day 0 (prior to dosing) and Day 14, blood was collected into tubes with sodium citrate for collection of plasma. Plasma samples were analyzed for mouse fibrinogen levels by ELISA (Molecular Innovations Mouse Fibrinogen Antigen ELISA kit, Cat# MFBGNKT) according to the manufacturer’s instructions. Fibrinogen values for all mice were normalized to that mouse’s Day 0 value. Results are shown in Table 171. Injection of mice with an alternatively modified version of ETD01841, namely ETD02481, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD01841. Injection of mice with alternatively modified versions of ETD02341, namely ETD02577 and ETD02578, resulted in lower relative levels of mean plasma fibrinogen relative to mice receiving ETD02341.

[00522] Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog# AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver FGG mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog# 101419-222). Data were normalized to the mean FGG mRNA level in animals receiving a subcutaneous injection of PBS. Results are shown in Table 172. None of the mice injected with alternatively modified versions of ETD01841 had lower relative levels of mouse liver FGG mRNA. None of the mice injected with alternatively modified versions of ETD02341 had lower relative levels of mouse liver FGG mRNA.

Table 169. Example siRNA Sequences

Table 170. Example siRNA BASE Sequences

Table 171. Fibrinogen Levels in Plasma of Mice Treated With siRNAs Targeting FGG

Table 172. Relative FGG mRNA Levels in Livers of Mice

Example 46: Inhibition of FGG in a Mouse Model for Depression Using Modified FGG siRNAs or

ASOs.

[00523] In this experiment, a mouse model of depression is used to evaluate the effect of siRNA or ASO-mediated inhibition of FGG. To induce depression like symptoms the mice will be subjected to Chronic Social Defeat (CSD) by repeated social confrontations with an aggressive mouse for 15 consecutive days. Depression-like symptoms are measured using Open Field Test, elevated T-maze and Tail Suspension Test.

[00524] Briefly, C57B1/6J mice (Charles River, MA USA) are divided into six groups: Group 1 -a group treated with non-targeting control siRNA, Group 2 - a group treated with non-targeting control ASO, Group 3 - a group treated with FGG siRNA, Group 4 - a group treated with FGG ASO, Group 5 - a group treated with vehicle, Group 6 - a group not subjected to chronic social defeat, treated with vehicle. Each group contains 20 male mice.

[00525] Administration of siRNA or ASO is achieved with a lOOpL subcutaneous injection of naked siRNA or ASO resuspended at concentration of 10 mg/mL in PBS. On Study Days 0, 7 and 21, Group 1 mice will be injected subcutaneously with non-targeting control siRNA, Group 2 mice will be injected subcutaneously with non -targeting control ASO, Group 3 mice will be injected subcutaneously with siRNA targeting mouse FGG, Group 4 mice will be injected subcutaneously with ASO targeting mouse FGG, and Group 5 and Group 6 mice will be injected subcutaneously with PBS.

[00526] All mice from groups 1-5 are exposed to CD-l/ICR mice (Charles River, MA USA), that have been previously screened for exhibiting aggressive behavior, for 15 days total beginning on Study Day 14. The behavioral tests are performed in Groups 1-5, 8 days after the final injection (Study Day 29). [00527] Mice are first evaluated using the open field paradigm (44x44x40 cm) in a sound-attenuated room. The total distance (cm) traveled by each mouse is recorded for 5 min by a video surveillance system (SMART; Panlab SL, Barcelona, Spain) and is used to quantify activity levels. The floor of the open-field apparatus is cleaned with 10% ethanol between tests.

[00528] The elevated T-maze is a behavioral test useful for screening potential antidepressant drugs and assessing other manipulations that are expected to affect anxiety related behaviors. Mice are placed individually in an apparatus that consists of three elevated arms, one enclosed and two open. Mice will be initially placed in the enclosed arm of the maze and the time taken to leave the enclosed arm in three consecutive trials is measured. The total time in enclosed is recorded as an index of anxiety-like behavior. [00529] The tail suspension test is a behavioral test useful for screening potential antidepressant drugs and assessing other manipulations that are expected to affect depression related behaviors. Mice are suspended by their tail, without the ability to escape or reach the sides of the enclosure. During the duration of the test, 6 minutes, the mouse’s escape -oriented behaviors will be quantified as well as time spend immobile. The total time spent attempting to escape versus time spent immobile is recorded as an index of depressive-like behavior.

[00530] 24 hours after the behavioral assessment, the mice are sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). A liver sample will be collected from all animals and placed in RNAlater™ Stabilization Solution (Thermo Fisher, Catalog# AM7020). The liver samples will be processed in homogenization buffer (Maxwell® RSC simplyRNA Tissue Kit) using Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, catalog# P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio™ 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice using the delta-delta Ct method. Plasma fibrinogen levels will be measured use the Clauss method or by ELISA according to the manufacturer’s instructions (Molecular Innovations Catalog# MFBGNKT).

[00531] A decrease in FGG mRNA expression in the liver tissue from mice dosed with the FGG siRNA or ASO is expected compared to FGG mRNA levels in the liver tissue from mice dosed with the non-specific controls. Measurement of plasma fibrinogen levels is expected to show a decrease in fibrinogen in the mice dosed with the FGG siRNA or ASO compared to fibrinogen from the plasma from mice dosed with non-specific control. There is an expected decrease in the time before the mice leave the enclosed arm of the elevated T-maze as well in a decrease in time spent in the enclosed arm in mice that receive the FGG siRNA or ASO compared to mice that receive non-specific control. In addition, there is an expected decrease in total immobility time in the tail suspension test along with no change in locomotor activity in the open field test in mice that receive the FGG siRNA or ASO compared to mice that receive non-specific control.

[00532] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and compositions within the scope of these claims and their equivalents be covered thereby.

IV. SEQUENCE INFORMATION

[00533] Some embodiments include one or more nucleic acid sequences in the following tables:

Table 173. Sequence information

Table 174. siRNA sequences

Table 175. Example FGG mRNA

Table 176. Examples of Modified siRNA Sequences

[ETL1] = GalNAc#! (shown connected 5’ to the sense strand)

Claims

CLAIMS What is claimed is:

1. A composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing measurement in the subject, relative to a baseline hearing measurement.

2. The composition of claim 1, wherein the hearing measurement comprises a pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions measurement.

3. The composition of any one of the preceding claims, wherein the hearing measurement is improved by at least 10%.

4. The composition of any one of the preceding claims, wherein the oligonucleotide inhibits the expression of FGG.

5. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 3621.

6. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a nucleoside base sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1-3484.

7. The composition of any one of the preceding claims, wherein the oligonucleotide comprises the nucleoside base sequence of any one of SEQ ID NOs: 1-3484.

8. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a modified intemucleoside linkage.

9. The composition of claim 8, wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

10. The composition of claim 8, wherein the modified intemucleoside linkage comprises a phosphorothioate linkage.

11. The composition of any one of the preceding claims, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages.

12. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a modified nucleoside.

13. The composition of claim 12, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’-O-methoxyethyl, 2'-O- alkyl, 2’-O-allyl, 2'-fluoro, 2'-deoxy, or a combination thereof.

14. The composition of claim 12, wherein the modified nucleoside comprises 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, 2'-O- dimethylaminoethoxyethyl’(2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

15. The composition of claim 12, wherein the modified nucleoside comprises a 2 ’-fluoro modified nucleoside.

16. The composition of claim 12, wherein the modified nucleoside comprises a 2’-O-alkyl modified nucleoside.

17. The composition of any one of the preceding claims, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

18. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

19. The composition of claim 18, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

20. The composition of claim 18, wherein the sugar comprises GalNAc.

21. The composition of claim 18, wherein the sugar moiety comprises ETL17.

22. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

23. The composition of any one of claims 1-21, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

24. The composition of any one of the preceding claims, further comprising a pharmaceutically acceptable carrier.

25. A method of treating a subject having a hearing disorder, comprising administering an effective amount of the composition of any one of the preceding claims to the subject.

26. The method of claim 25, wherein the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss.