CA3174172A1 - Compositions and methods for treating cancer - Google Patents

Abstract

A double stranded RNA interference (RNAi) agent comprising at least one of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, or (iii) a cocktail of (i) and (ii) and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA and the use of the RNAi agent as a pharmaceutical composition for the treatment of cancer in subjects in need of treatment.

Description

COMPOSITIONS AND METHODS FOR TREATING CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of the filing of U.S. Patent Application No. 17/359,905, filed on June 28, 2021, titled "Compositions and Methods for Treating Cancer". The specification and claims thereof are incorporated herein by reference.
SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 26, 2022, is named 32064-1035-PCT2_SL.txt and is 446,054 bytes in size.
BACKGROUND

[0003] A variety of cancer therapies and treatments exist such as surgical resection of solid tumors, radiation, and chemotherapy. While surgical resection and radiation are used on localized tumors, chemotherapy is often delivered systemically and impacts both cancer and non-cancer cells, leading to severe and even life-threatening side effects. Older cancer drugs, including alkylators, nucleotide antinnetabolites, and tubulin poisons, cause significant side effects because they are similarly toxic to normal cells as to cancer cells, especially those normal cells undergoing routine cell division in the intestine, scalp, and skin. For this reason, much of the effort in contemporary cancer drug discovery is devoted to finding targeted therapeutics which differentiate between cancer cells and normal cells (Neidle et al., (2014) Cancer Drug Design and Discovery).
This has led to drugs which inhibit the function of oncolytic proteins that are mutated, overexpressed, or abnormally hyperactive in cancer but not in normal cells. Examples of such drugs include kinase inhibitors, histone deacetylase inhibitors, proteasonne inhibitors, nnTOR inhibitors, BCL2 inhibitors, and isocitrate dehydrogenase inhibitors. Significant effort has also been devoted to targeting cell surface antigens which are differentially expressed in cancer cells compared to normal cells.
Monoclonal antibodies and antibody-drug conjugates targeting cancer cell surface antigens have thus been developed as cancer therapeutics (Beck et al., (2017) Nat Rev Drug Disc 16, 315-337).
Another point of differentiation between cancer cells and normal cells is metabolism. It was discovered many years ago that many cancer cells utilize glucose fermentation to generate ATP as opposed to the process of oxidative phosphorylation used by normal cells. A drug targeting isocitrate dehydrogenase, involved in abnormal glucose metabolism in cancer cells, was recently approved by the FDA (Dhillon (2018) Drugs 78, 1509-1516). Abnormalities in one-carbon metabolism, which encompasses the folate and nnethionine cycles and affects nucleotide synthesis and DNA nnethylation as a way of controlling gene expression, are strongly associated with some cancers (Fanidi et al., (2019) Int J Cancer 145, 1499-1503; Yang (2018) Front Oncol 8, 493). In this connection, it has been known for a long time that certain synthetic analogs of folic acid (antifolates) can inhibit the growth of cancer cells. It is also known that some cancer cells are dependent for survival on the amino acid methionine. If methionine is restricted, the cancer cells die, while this has little effect on normal cells. In recent years, evidence has begun to emerge that some cancer cells might have an abnormal dependency on vitamin B12.
The nature of this dependency is not understood but might, in part, involve the use of vitamin B12 as a catalytic cofactor by the enzyme methionine synthase in one-carbon metabolism.

[0004] Vitamin B12 (cobalamin) is an essential micronutrient in the human diet. It is a cofactor for the metabolic enzymes methionine synthase and nnethylnnalonyl-CoA
nnutase (Fedosov et al., (2012) Water Soluble Vitamins (book) 56, 347-367). After oral ingestion and transport through the intestine, cobalannin is almost completely protein bound in plasma to the chaperone proteins transcobalannin 1 (TCN1, haptocorrin, R-binder) (TC01_HUMAN) and transcobalamin 2 (TCN2) (TCO2_HUMAN). The TCN2-cobalamin complex (TCN2-Cbl) is taken up by most cells using the process of receptor-mediated endocytosis and has a plasma half-life of 1-15 h.
TCN2 has a high affinity and specificity for cobalannin in its various dietary and nutritional supplement forms, such as methyl cobalannin, adenosyl cobalannin and cyanocobalannin (Fedosov et al., (2007) Biochenn 46, 6446-6458). TCN1 is a glycoprotein that exists in two different forms in plasma (Marzolo and Farfan (2011) Biol Res 44, 81-105). The most abundant form is sialylated and has a plasma half-life of about days (Bor (2004) Clin Chem 50, 1043-1049). A less abundant form is desialylated and has a plasma half-life of a few minutes. Unlike TCN2-Cbl, which can be taken up by almost all cell types, the transcobalannin 1-cobalannin complex (TCN1-Cb1) is quickly taken up by certain liver cells, only in its desialylated form, by receptor-mediated endocytosis.

[0005] CD320 and LRP2 are two receptors involved in the uptake of cobalannin as TCN2-Cbl. CD320, a member of the low-density lipoprotein receptor (LDLR) family, is constitutively expressed in most cells and is the receptor primarily responsible for the uptake of cobalannin (Quadros (2013) Biochinnie 95, 1008-1018). CD320 is overexpressed in some types of cancer (Sycel et al., (2013) Anticancer Res 33, 4203-4212; Amagasaki (1990) Blood 76, 1380-1386). There is also evidence that CD320 facilitates the transport of TCN2-Cbl through the blood-brain barrier into the brain (Lai et al.; (2013) FASEB 27, 2468-2475). LRP2 is another receptor in the LDLR family. It is expressed most highly in the kidney but also in other tissues. In addition to cobalannin, LRP2 also transports sundry proteins and small molecules, induding albumin, insulin and vitamin D (Mazolo et al., (2011) Biol Res 44, 89-105). In the liver, the asialoglycoprotein receptor (ASGR) uptakes TCN1-Cbl by receptor-mediated endocytosis so long as TCN1 is in its desialylated form. Normal liver cells and liver cancer cells express very high levels of ASGR (-50,000 receptors per cell), making this receptor attractive as a portal for delivering drugs to the liver (Luo et al., (2017) Biomedicine and Pharnnacotherapy 88, 87-94; Stockert (1995) Physiological Rev 75, 595-609;
Soda et al., Blood (1985) 65, 795-802).

[0006] After receptor mediated endocytosis, cobalannin is sequestered in the endosonne, where the endosonnal membrane prevents passive egress to the cytosol. A
specialized protein (cbIF) facilitates the transport of cobalannin through the endosonnal membrane to the cytosol (Banerjee et al., (2009) Curr Opin Chem Bio 13,484-491).
BRIEF SUMMARY OF THE INVENTION

[0007] One embodiment of the present invention provides for a double stranded RNA
interference (RNAi) agent comprising at least one of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA
comprises a sense strand and an antisense strand forming a duplex, (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, or (iii) a cocktail of (i) and (ii) and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA.
For example, the antisense strand of (i) the first dsRNA includes a region of connplennentarity to a CD320 RNA transcript and for example the sense strand of (i) the first dsRNA
is selected from Table 5. The antisense strand of (ii) the second dsRNA includes a region of complementarity to an LRP2 RNA transcript and the sense strand of (ii) the second dsRNA are selected from Table 6. In one example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 16-30 nucleotide pairs in length. In another example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 21-23 nucleotide pairs in length. In one embodiment, the double stranded RNAi agent includes at least one strand of: (i) the first dsRNA or (ii) the second dsRNA which comprises a 3 overhang of at least 2 nucleotides. Further still, in one embodiment, the antisense strand of (i) the first dsRNA, comprises the nucleotide sequence selected from (5' 4 3'):CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17);
CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT (SEQ ID NO 18);
mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU
nnCdT*dT (SEQ ID NO 19);
mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU
mC (SEQ ID NO 21);
mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU
nnCdT*dT (SEQ ID NO 23);
mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fU
mCdT*dT (SEQ ID NO 24);
mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fU
nnC (SEQ ID NO 25);
2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2fAmG2fUmU
2fCdT*dT (SEQ ID NO 28);
2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2fAmG2fUmU
2fC (SEQ ID NO 29);
mC2fA2fG2fU2fU2fG2fC2fG2fC2fA2fG2fU2fU2fU2fC2fU2fU2fG2fU2fC2fA2fG2fU2fU

2fCdT*dT (SEQ ID NO 30);
mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fU
mCdT*dT (SEQ ID NO 32);
mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU (SEQ ID NO 33);
mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fU2fU2fG2fU2fC2fA2fG2fU (SEQ ID NO 34);
wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

[0008] Further still, in another embodiment, the double stranded RNAi agent indudes the antisense strand of (i) the first dsRNA, that comprises the nucleotide sequence selected from (5' 4 3') AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64);
AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65);
mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAnnGnnGnnGdT*dT (SEQ ID NO 66);
mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGnnAnnGnnGnnG (SEQ ID NO 68);
mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmGdT*dT (SEQ ID NO 71);
mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmG (SEQ ID NO 72);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO 75);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 76);
mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 77);
mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO 78);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO 79);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fC2fU2fG2fA2fG2fG2fG (SEQ ID NO 81);
wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

[0009] In another embodiment the double stranded RNAi agent of (h) the second dsRNA
comprises the nucleotide sequence selected from (5' 4 3') UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417);
UUUGAUAGCACCAAACCUAGAGCCCdT*dT (SEQ ID NO: 418);
mUm[mUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmC
dT*dT (SEQ ID NO: 419);
mUmUmUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmC (SEQ ID NO:
421);
mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmCdT*dT](SEQ
ID NO: 424);

mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmC (SEQ ID NO:
425);
mU2fAmU2fCmA2fAmA2fCmC2fUmC2fGmA2fUmA2fGmC2fAmA2fCmA2fCmC2fGmC (SEQ ID NO:
429);
mU2fU2fU2fG2fA2fU2fA2fG2fC2fA2fC2fC2fA2fA2fA2fC2fC2fU2fA2fG2fA2fG2fC2fC2fCdT*dT
(SEQ
ID NO: 430);
mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmCdT*dT (SEQ
ID NO: 432);
mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC (SEQ ID NO: 433);
and mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fC2fC2fU2fA2fG2fA2fG2fC (SEQ ID NO: 434) wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

[0010] In a further embodiment, the double stranded RNAi agent antisense strand of (h) the second dsRNA comprises the nucleotide sequence selected from (5' 4 3') UUUGCAAUGACUCUCCUAUCAGUCCdTdT(SEQ ID NO: 448);
UUUGCAAUGACUCUCCUAUCAGUCCdT*dT (SEQ ID NO: 449);
mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAnnGnnUnnCnnCdT*dT (SEQ
ID NO: 450);
mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmC (SEQ ID NO:
452);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdT*dT (SEQ
ID NO: 455);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmC (SEQ ID NO:
456);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fCmU2fC
nnC (SEQ ID NO: 458);
2fUmU2fUmG2fCmA2fAmU2fGmA2fCmU2fCmU2fCmC2fUmA2fUmC2fAmG2fUmC2fCdT*dT (SEQ
ID NO: 459);
mU2fAmU2fCmC2fUmA2fAmG2fUmC2fAmC2fAmC2fGmU2fUmU2fGmA2fCmU2fGmC (SEQ ID NO:
460);
mU2fU2fU2fG2fC2fA2fA2fU2fG2fA2fC2fU2fC2fU2fC2fC2fU2fA2fU2fC2fA2fG2fU2fC2fCdT*dT
(SEQ
ID NO: 461);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdT*dT (SEQ
ID NO: 463);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU (SEQ ID NO: 464);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fC2fU2fA2fU2fC2fA2fG2fU (SEQ ID NO: 465) wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

[0011] For example, when the RNAi agent comprises (iii) the combination of (i) the first dsRNA and (ii) the second dsRNA, the antisense strand of (i) the first dsRNA
is selected from CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17);
CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT (SEQ ID NO 18);
AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64); and AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65); and the antisense strand of (ii) the second dsRNA is selected from UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417);
UUUGAUAGCACCAAACCUAGAGCCCdT*dT (SEQ ID NO: 418);
UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 448); and UUUGCAAUGACUCUCCUAUCAGUCCdT*dT (SEQ ID NO: 449);
wherein * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

[0012] In one embodiment, (i) the first dsRNA has the duplex structure of (SEQ ID NOs: 17 and 110) or (SEQ ID NOs: 18 and 111). In another (ii) the second dsRNA has the duplex structure of (SEQ ID NOs: 417 and 808) or (SEQ ID NOs: 448 and 822).

[0013] Another embodiment provides for an isolated cell comprising a double stranded RNAi gent of (i), (ii) or (iii).

[0014] For example, the sense strand of (i) the first dsRNA
is no more than 30 nucleotides in length, and the antisense strand of (i) the first dsRNA is no more than 30 nucleotides in length. For example, the sense strand of (ii) the second dsRNA is no more than 30 nucleotides in length, and the antisense strand is no more than 30 nucleotides in length.

[0015] Yet another embodiment provides a pharmaceutical composition for inhibiting expression of a CD320 gene, the pharmaceutical composition comprising a double stranded RNAi agent (i) or (iii). Further the pharmaceutical composition may include an excipient.

[0016] Yet another embodiment provides a pharmaceutical composition for inhibiting expression of an LRP2 gene, the composition comprising a double stranded RNAi agent (ii) or (iii).
Further the pharmaceutical composition may include an excipient.

[0017] Another embodiment of the present invention provides a method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit proliferation of the CC. For example, the CC may express CD320 and/or LRP2 or both.

[0018] Another embodiment of the present invention provides a method for treating a therapeutically-resistant cancer in a subject who has previously received a therapy, comprising administering to the subject an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit or kill cancer cells (CCs) present in the therapeutically-resistant cancer.

[0019] Another embodiment of the present invention provides a method for treating cancer in a subject who has recurring or relapsed cancer comprising administering to a subject an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit or kill CCs in the cancer.

[0020] The CC is from a cancer selected from melanoma, glioblastonna, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

[0021] The CD320 inhibitor is selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid sequence encoding CD320.

[0022] Further, the method of inhibiting proliferation of a CC, treating a therapeutically resistive cancer in a subject or has a recurring or relapsed cancer comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA
encoding for CD320 or an RNAi agent that hybridizes to an mRNA encoding for LRP2. For example, the cancer therapeutic is selected from the antifolate class, epigenetic modulatory class, or a small molecule or protein inhibitor of CD320 function or LRP2 function, such as an antibody for CD320 or an antibody for LRP2. Further still, the method further comprises administering mefformin. For example, the RNAi agent comprises an antisense strand of Table 5 or of Table 6.

[0023] The inhibitor is selected from the group consisting of an antibody that binds LRP2, a small molecule inhibitor of LRP2, and an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2. For example, the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class, or the small molecule or protein inhibitor of LRP2 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

[0024] The method further comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

[0025] One embodiment of the present invention provides for a method for inhibiting proliferation of a cancer cell (CC) comprising contacting of a CC with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective to inhibit proliferation of the CC.
For example, the composition is a cocktail comprising i) the CD320 inhibitor selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid encoding CD320 and any combination thereof, and ii) the LRP2 inhibitor selected from an antibody that binds LRP2, a small molecule inhibitor of LRP2, and a RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2 and any combination thereof. Further, the method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class. For example, the RNAi agent that hybridizes to the mRNA
encoding for CD320 comprises a first double-stranded ribonucleic acid (dsRNA) for inhibiting expression of CD320, wherein the first dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complennentarity to a CD320 RNA transcript and the RNAi agent that hybridizes to the mRNA encoding for LRP2 comprises a second dsRNA for inhibiting expression of LRP2, wherein the second dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an LRP2 RNA transcript. In a further example, the antisense strand that is complementary to CD320 RNA transcript is selected from Table 5 and the antisense strand that is complementary to the RNA transcript for LRP2 is selected from Table 6. The method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class. The method further comprises administering a cancer therapeutic selected from the innnnunonnodulatory class. Further still, the method further comprises administering nnefformin.

[0026] One aspect of one embodiment of the present invention provides a method for the inhibition of CD320 and LRP2 protein expression, such that the levels of these proteins are reduced in treated cells compared to their endogenous levels in untreated cells; this inhibition may also be referred to as the knockdown of CD320 and LRP2 expression. The method entails the use of a cocktail of small interfering RNA molecules, otherwise known as siRNAs, which guide the mRNA
sequences encoding for either CD320 or LRP2 into an enzymatic complex which leads to targeted destruction of these mRNAs.

[0027] Another aspect of the present invention provides a method for the individual or concurrent inhibition of LRP2 and CD320 protein expression, which inhibits the growth of many cancer cells as compared to non-cancer (normal) cells. In some instances, CD320 or LRP2 protein knockdown alone is sufficient to severely inhibit cancer cell proliferation compared to normal cells.

[0028] Another aspect of the present invention provides for inhibition of cancer cell proliferation by inhibiting LRP2 receptor expression.

[0029] Mechanistic investigations into the selectivity of porphyrin uptake by cancer cells led to several nonobvious compounds and methods of using the compound(s). It was discovered that the knockdown of the expression of either CD320 gene or LRP2 gene or the simultaneous knockdown of the expression of CD320 gene and LRP2 gene caused cell death or inhibition of cell growth in a panel of lung cancer cell lines, compared to normal fibroblasts. The experimental outline is illustrated in FIG. 1. In these experiments, cells were plated on day 0. The next day (day 1), virus particles encoding short hairpin RNAs (shRNAs) directed to the CD320 gene and the LRP2 gene or an irrelevant shRNA control were added to the cell culture together with protannine sulfate, a reagent that facilitates cell entry of the virus particles.

[0030] Further investigations revealed that knockdown of the expression of either the CD320 gene or LRP2 gene or the simultaneous knockdown of the expression of CD320 and LRP2 genes using small interfering RNAs (siRNAs) caused cell death or inhibition of cell growth in a panel of cancer cell lines that included lung cancer, prostate cancer, breast cancer, glioblastonna and melanoma, compared to normal fibroblasts (FIG. 9-10). It was also found that that knockdown of one gene, either CD320 or LRP2, led to increased expression of the other in some cancer cell lines.

[0031] One aspect of the present invention provides for the knockdown of the CD320 receptor, the LRP2 receptor or the simultaneous knockdown of both in vivo and in vitro cancer cells that express CD320 mRNA and/or LRP2 mRNA.

[0032] Another aspect of the present invention is a method to inhibit cell growth or cause cell death of cancer cells treated with a compound as described herein, while leaving normal cells unaffected or inhibiting cell growth to a lesser degree or producing less cell death as compared to a cancer cell treated with the same amount of the compound.

[0033] Another aspect of a first compound and method of use is a selective therapy which inhibits proliferation of cancer cells and/or kills cancer cells with an inhibition of LRP2 Receptor while leaving normal cells unharmed.

[0034] Another aspect of a second compound and method of use is a selective therapy which inhibits proliferation of cancer cells and/or kills cancer cells with an inhibition of CD320 Receptor while leaving normal cells unharmed.

[0035] Another aspect of the present invention provides for treating a cancer by administering a therapy to selectively inhibit proliferation of a cancer cell(s) and/or kill a cancer cell(s) with one or more of the following, a first compound that is an inhibitor of CD320 receptor, a second compound that is an inhibitor of LRP2 receptor or a combination thereof.
DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0036] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating one or more embodiments of the invention and are not to be construed as limiting the invention. In the drawings:

[0037] FIG. 1 illustrates an experimental design for knocking down CD320 and LRP2 in a cell.
Cells were plated on day 0. The next day (day 1), virus particles encoding short hairpin RNAs (shRNAs) directed at the CD320 and LRP2 nnRNA or a non-targeting shRNA control were added to the cell culture together with protannine sulfate, a reagent that facilitates cell entry of the virus particles. Table 1 shows the sequences that were used. Each shRNA coding sequence was also combined with a unique drug resistance gene, which would allow for selecting those cells that had taken up the shRNA; cells that had not taken up the shRNA would not survive.
On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. Cells infected with the non-targeting negative control shRNA continued growing ¨
data not shown. The results for the cell lines that expressed the CD320+LRP2 shRNAs are shown in Table 1.

[0038] FIG. 2 A-C illustrates sensitivity of cancer cell lines to knockdown of CD320 and LRP2. Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1.
The cells were grown as described in FIG. 1. On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid oval indicates healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cancer cells infected with shRNAs targeting CD320 and LRP2 (FIG. 2A). The fields of cells in FIG. 2A were counted and quantified and illustrated in FIG. 2B. The data in FIG. 2B were normalized to the number of control cells and illustrated in FIG. 2C. FIG. 2C. shows that the cultures of cells infected with lentivirus encoding the shRNAs against CD320 and LRP2 (white bars) contain far fewer cells than the cultures of cells exposed to the shRNA control (black bar).

[0039] FIG. 3 A-F illustrate graphs of protein levels resulting from transfection of HEK293, MDA-MB-435S and MDA-MB-231 cells with siRNA to LRP2 and CD320. HEK293, MDA-MB-and MDA-MB-231 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours.
siRNAs targeting CD320 are designated OSC17 and 0SC47. siRNAs targeting LRP2 are designated 0SL245, 0SL47, OSL104, OSL90 and OSL119. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIG. 3 A-F represent the fold change of protein levels compared to siScrannble (OSS1 or OSS2).
(Average +1- SEM is shown, n=3).

[0040] FIG. 4 A-F illustrate a graph of cells after transfection of LnCAP, MCF-7 and U251 cells with siRNA to LRP2 and CD320. LnCAP, MCF-7 and U251 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and 0SC47. siRNAs targeting LRP2 are designated 0SL245, 0SL47, OSL104, OSL90 and OSL119).
Whole cell lysates were prepared and innnnunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA
transfection. The graphs FIG. 4 A-F represent the fold change of protein levels compared to siScrannble (OSS2).

[0041] FIG. 5A-C illustrate graphs of protein levels after transfection of A172, DU145 and GM05659 cells with siRNA to LRP2 and CD320. A172, DU145 and GM05659 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and 0SC47. siRNAs targeting LRP2 are designated 0SL245, 0SL47, OSL104, OSL90 and OSL119). Whole cell lysates were prepared and innnnunoblotted for CD320. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA
transfection. The graphs FIG.
5A-C represent the fold change of protein levels compared to siScrannble (0552).

[0042] FIG. 6 illustrates a graph of relative LRP2 protein expression in various cell lines ¨
Lysates were made from the cell lines indicated on the x-axis, and western blot was performed to determine LRP2 protein levels. The results represent the averages +/-SEM of three independent lysates.

[0043] FIG. 7 A-B illustrates graphs of the effect of doxorubicin treatment on cell viability, as measured by the CTG assay. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate.
The next day, cells were treated with doxorubicin at the indicated concentrations. Four days after doxorubicin treatment was initiated, the cells were assayed for viability using the CTG assay. The dashed line indicates the non-linear fitting of the data to calculate an IC50 value.

[0044] FIG. 8 is a schematic overview of the functional assay for screening siRNA effects on cell proliferation to facilitate quantification of the effects of knocking down CD320 and LRP2 on cell proliferation. Cells were plated in a 24-well plate. The next day, the cells were transfected with siRNAs targeting CD320 (OSC17, 0SC47) and/or targeting LRP2 (0SL231, 05L245), or a control siRNA (OSS2). The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. In addition, in a small subset of the wells, cells were only treated with doxorubicin as a positive control for toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay.

[0045] FIG. 9 A-E illustrate graphs of the percent cell survival of siCD320 and siLRP2 on cell proliferation ¨ Cell lines representative of several types of cancers (lung, brain) or normal fibroblasts were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, 0SC47) or LRP2 (0SL231, 0SL245), individually at 20 nM or in combination (10 nM each), or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0046] FIG. 10 A-E illustrate graphs of the effects of siCD320 and siLRP2 on cell proliferation ¨ Cell lines representative of several types of cancers (breast, prostate, skin) were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, 0SC47) or LRP2 (0SL231, 0SL245) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0047] FIG. 11A-B illustrate the effects of siCD320 and siLRP2 molar proportions on cell proliferation with different molar proportions of siRNA targeting CD320 and siRNA targeting LRP2.
Cell lines representative of two types of cancers (breast, prostate) were transfected with different proportions of siRNAs targeting CD320 (OSC17) or LRP2 (0SL245) (0-20 nM) or a negative control siRNA (OSS2) as indicated. Cells were repeatedly transfected for efficient toxicity then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0048] FIG. 12A-B illustrate graphs of the duration of the knockdown effect for siCD320 and siLRP2 on MDA-MD-231 cells. A representative breast cancer cell line (MDA-MD-231) was transfected on Day 0 with 20 nM of an siRNA targeting CD320 (OSC17) or an siRNA targeting LRP2 (0SL245) or a negative control siRNA (OSS2) and the percentage of protein knockdown was analyzed daily over a period of five days by western blot. Protein levels were normalized to the negative control (OSS2).

[0049] FIG. 13 is a schematic of polyethylinimine (PEI) and siRNA complexation. PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) of the PEI-siRNA complex form, which are able to enter the cell.

[0050] FIG. 14 is a schematic that illustrates that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the guide sequence of the siRNA is complementary to a mRNA
expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are separated via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule.
The mRNA is degraded by the RISC/AGO complex, which has RNAse activity, resulting in mRNA
degradation, and the protein encoded by the mRNA is not produced. This causes the "knockdown"
effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

[0051] FIG. 15 A-B illustrate graphs of A172 cell line or MDA-MD-435S cell lines treated with control siRNA (OSS1, OSS2) and siRNA directed to CD320 nnRNA (OSC17, 0SC47) and siRNA
directed to LRP2 nnRNA (0SL231, 0SL245) to determine the effectiveness of INTERFERin, a polyethanolannine transfection reagent, in delivering siRNAs to cancer cells.

[0052] FIG. 16 A-D illustrate plated cells showing the effects of siCD320 and siLRP2 on four cell lines. Cell lines representative of four types of cancers (breast, two prostate, skin) were transfected with siRNAs targeting CD320 (OSC17) or LRP2 (0SL245) individually at 20 nM or in combination (10 nM each) or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected for efficient toxicity as in Table 9 and then analyzed by microscopy as indicated.

[0053] FIG. 17 illustrates a graphical depiction of CD320 nnRNA. UTR references the untranslated region, and the CDS references the protein coding sequence.

[0054] FIG. 18 illustrates a graphical depiction of LRP2 mRNA UTR references the untranslated region, and the CDS references the protein coding sequence.

[0055] FIG. 19A-G illustrates the structures for unnatural nudeotides which may be incorporated within the sequence of an RNAi. "B" represents a natural (G, C, A, U) RNA nudeobase, a DNA nucleobase, or an unnatural nucleobase. FIG. 19A shows certain chemical modifications to the ribose 2'-position and phosphate moieties. FIG. 19B-D shows skeletal modifications to the ribose moiety that comprise bridging groups. FIG. 19E shows a deletion of the C2'-C3' bond. FIG. 19F-G
shows other skeletal modifications to the ribose moiety wherein a six-membered ring replaces the five-membered ring.

[0056] FIG. 20 illustrates a schematic for the in vivo nnurine xenograft model for breast cancer. MDA-MB-231 cells were implanted into the flank of NSG mice and grown to a volume of 70 mm3 after which siRNAs targeting CD320 (OSC17) and LRP2 (0SL245) were injected intratunnorally once every fourth day.
DETAILED DESCRIPTION OF THE INVENTION

[0057] One or more embodiment of the present invention provides methods and RNAi compounds for modulating the expression of a CD320 gene and/or an LRP2 gene in a cell. In certain embodiments, expression of a CD320 gene and/or a LRP2 gene is reduced or inhibited using an CD320 and/or LRP2 specific RNAi. Such inhibition can be useful in treating disorders such as cancer and/or creating cell lines that are useful for screening drugs that treat cancer

[0058] The present invention also relates to a method for knocking down (partially or completely) the targeted genes.

[0059] One embodiment of the method of producing knockdown cells and organisms comprises introducing into a cell or organism in which a gene (referred to as a targeted gene) to be knocked down, an siRNA of about 16 to about 30 nucleotides (nt) that targets the gene and maintaining the resulting cell or organism under conditions under which RNAi occurs, resulting in degradation of the nnRNA of the targeted gene, thereby producing knockdown cells or organisms.
Knockdown cells and organisms produced by the present method are also the subject of embodiment of the present invention.

[0060] An embodiment of the present invention also relates to a method of examining or assessing the function of a gene in a cell or organism. In one embodiment, RNA
of about 16 to about 30 nt which targets nnRNA of the gene for degradation is introduced into a cell or organism in which RNAi occurs. The cell or organism is referred to as a test cell or organism.
The cell or organism is referred to as a test cell organism. The test cell or organism is maintained under conditions under which degradation of nnRNA of the gene occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control cell or organism, such as a corresponding cell or organism that is treated in the same manner except that the gene is not targeted. A 16 to 30 nt RNA that does not target the nnRNA for degradation can be introduced into the control cell or organism in place of the siRNA introduced into the test cell or organism, although it is not necessary to do so. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the degraded nnRNA.

[0061] The RNA of about 16 to about 30 nucleotides is isolated or synthesized and then introduced into a cell or organism in which RNAi occurs (test cell or test organism). The test cell or test organism is maintained under conditions under which degradation of the nnRNA occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control, such as a corresponding cell or organism that is treated in the same manner as the test cell or organism except that the targeted gene is not targeted. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the targeted gene. The information provided may be sufficient to identify (define) the function of the gene or may be used in conjunction with information obtained from other assays or analyses to do so.

[0062] An embodiment of the present invention also encompasses a method of treating a disease or condition associated with the presence of a protein in an individual, comprising administering to the individual RNA of from about 16 to about 30 nucleotides which targets the nnRNA
of the protein (the nnRNA that encodes the protein) for degradation. As a result, the protein is not produced or is not produced to the extent it would be in the absence of the treatment.

[0063] FIG. 14 shows that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides;
the sequence of the siRNA is complementary to a nnRNA expressed in the cell.
Exogenous siRNA
duplexes are introduced into the cell via a method of transfection. The siRNA
duplexes are unwound via the RNA-induced silencing complex (RISC), whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The nnRNA is degraded by the RISC/AGO
complex, which has RNAse cleave activity. The end result is that the nnRNA targeted by the siRNA is degraded, and the protein encoded by the nnRNA is not produced. This causes the "knockdown"
effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

[0064] In one embodiment, at least one strand of the RNA
molecule has a 3 overhang from about 1 to about 6 nucleotides (e.g., pyrinnidine nucleotides, purine nucleotides) in length. In other embodiments, the 3' overhang is from about 1 to about 5 nucleotides, from about 1 to about 3 nucleotides and from about 2 to about 4 nudeotides in length or, for example, the overhang can be up to 14 nucleotides if the guide strand were a 27-nner. In one embodiment the RNA molecule is double stranded, one strand has a 3' overhang and the other strand can be blunt-ended or have an overhang. In the embodiment in which the RNA molecule is double stranded and both strands comprise an overhang, the length of the overhangs may be the same or different for each strand. In a particular embodiment, the RNA of the present invention comprises 21-27 nucleotide strands which are Watson-Crick paired and which have overhangs of from about 1 to about 3, particularly about 2, nucleotides on both 3' ends of the RNA. In order to further enhance the stability of the RNA of the present invention, the 3' overhangs can be stabilized against degradation. In one embodiment, the RNA is stabilized by induding purine nucleotides, such as adenosine or guanosine nucleotides.
Alternatively, substitution of pyrinnidine nucleotides by unnatural nucleotides, e.g., substitution of uridine 2 nucleotide 3' overhangs by 2'-deoxythynnidine, is tolerated and does not affect the efficiency of RNAi. The absence of a 2' hydroxyl significantly enhances the nuclease resistance of the overhang in tissue culture medium. The 3'-overhangs can be further stabilized by introduction of phosphorothioate groups in place of the phosphodiesters.

[0065] The 16-30 nt RNA molecules of the present invention can be obtained using a number of techniques known to those of skill in the art. For example, the RNA
can be chemically synthesized or reconnbinantly produced using methods known in the art.

[0066] In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention.

[0067] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element, e.g., a plurality of elements.

[0068] The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to".

[0069] The term "or" is used herein to mean, and is used interchangeably with, the term "and/or," unless context clearly indicates otherwise.

[0070] As used herein, "CD320 " refers to the gene or protein. CD320 is also known as 8D6 antigen, CD320 antigen, 8D6A, transcobalalnnin receptor, FDC-SM-8D6, FDC-Signaling Molecule 8D6, 8D6, TCBLR, TCbIR, TCN2R. The term CD320 includes human CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_016579.4 and NM_001165895.2; mouse CD320, the amino acid and nudeotide sequence of which may be found in, for example, GenBank Accession No. NM_019421.3; rat CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No.
NM_001014201.1. Additional examples of CD320 nnRNA sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 17.

[0071] The CD320 DNA sequence from honno sapiens is as follows: >NM_016579.4 Homo sapiens CD320 molecule (CD320), transcript variant 1, DNA
GTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCGGCGCCGCTGTGGGGACAGCATGA
GCGGCGGTTGGATGGCGCAGGTTGGAGCGTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCT
CGGCCTCGGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTCTGCCCAGGCCGCAGGC
CCCAGCTCAGGCTCGTGCCCACCCACCAAGTTCCAGTGCCGCACCAGTGGCTTATGCGTGCCCCTCACCT
GGCGCTGCGACAGGGACTTGGACTGCAGCGATGGCAGCGATGAGGAGGAGTGCAGGATTGAGCCATGTAC
CCAGAAAGGGCAATGCCCACCGCCCCCTGGCCTCCCCTGCCCCTGCACCGGCGTCAGTGACTGCTCTGGG
GGAACTGACAAGAAACTGCGCAACTGCAGCCGCCTGGCCTGCCTAGCAGGCGAGCTCCGTTGCACGCTGA
GCGATGACTGCATTCCACTCACGTGGCGCTGCGACGGCCACCCAGACTGTCCCGACTCCAGCGACGAGCT
CGGCTGTGGAACCAATGAGATCCTCCCGGAAGGGGATGCCACAACCATGGGGCCCCCTGTGACCCTGGAG
AGTGTCACCTCTCTCAGGAATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAGTGTCCCCTCTGTCG
GGAATGCCACATCCTCCTCTGCCGGAGACCAGTCTGGAAGCCCAACTGCCTATGGGGTTATTGCAGCTGC
TGCGGTGCTCAGTGCAAGCCTGGTCACCGCCACCCTCCTCCTITTGTCCTGGCTCCGAGCCCAGGAGCGC
CTCCGCCCACTGGGGTTACTGGTGGCCATGAAGGAGTCCCTGCTGCTGTCAGAACAGAAGACCTCGCTGC
CCTGAGGACAAGCACTTGCCACCACCGTCACTCAGCCCTGGGCGTAGCCGGACAGGAGGAGAGCAGTGAT
GCGGATGGGTACCCGGGCACACCAGCCCTCAGAGACCTGAGCTCTTCTGGCCACGTGGAACCTCGAACCC
GAGCTCCTGCAGAAGTGGCCCTGGAGATTGAGGGTCCCTGGACACTCCCTATGGAGATCCGGGGAGCTAG
GATGGGGAACCTGCCACAGCCAGAACTGAGGGGCTGGCCCCAGGCAGCTCCCAGGGGGTAGAACGGCCCT
GTGCTTAAGACACTCCTGCTGCCCCGTCTGAGGGTGGCGATTAAAGTTGCTTCACATCCTCAAAAAAAAA

AAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO. 935).

[0072] A protein sequence from CD320 derived from the nnRNA
sequence above is as follows: >splQ9NPFOICD320_HUMAN CD320 antigen OS=Honno sapiens OX=9606 GN=CD320 PE=1 SV=1 MSGGWMAQVGAWRTGALGLALLLLLGLG LGLEAAASPLSTPTSAQAAGPSSGSCPPTKFQ
CRTSG LCVPLTW RCDRDLDCSDGSDEE ECRI EPCTQKGQCP P P PGLPCPCTGVSDCSGGT
DKKLRNCSRLACLAG ELRCTLSDDCI PLTWRCDG HP DCPDSSDE LGCGTN El LP EG DATT
MG PPVTLESVTSLR NATTM G P PVTLESVPSVG NATSSSAG DQSGSPTAYGVIAAAAVLSA
SLVTATLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP (SEQ ID NO. 936)

[0073] The CD320 DNA sequence from honno sapiens is as follows: > NM_001165895.2 Homo sapiens CD320 molecule (CD320), transcript variant 2, DNA
GCGTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCGGCGCCGCTGTGGGGACAGCAT
GAGCGGCGGTTGGATGGCGCAGGTTGGAGCGTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGC
TCGGCCTCGGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTITCCACCCCGACCTCTGCCCAGGCCGCAGGGA
TTGAGCCATGTACCCAGAAAGGGCAATGCCCACCGCCCCCTGGCCTCCCCTGCCCCTGCACCGGCGTCAGTGA
CTGCTCTGGGGGAACTGACAAGAAACTGCGCAACTGCAGCCGCCTGGCCTGCCTAGCAGGCGAGCTCCGTTG
CACGCTGAGCGATGACTGCATTCCACTCACGTGGCGCTGCGACGGCCACCCAGACTGTCCCGACTCCAGCGAC
GAGCTCGGCTGTGGAACCAATGAGATCCTCCCGGAAGGGGATGCCACAACCATGGGGCCCCCTGTGACCCTG
GAGAGTGTCACCTCTCTCAGGAATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAGTGTCCCCTCTGTCG
GGAATGCCACATCCTCCTCTGCCGGAGACCAGTCTGGAAGCCCAACTGCCTATGGGGTTATTGCAGCTGCTGC
GGTGCTCAGTGCAAGCCTGGTCACCGCCACCCTCCTCCTTTTGTCCTGGCTCCGAGCCCAGGAGCGCCTCCGCC
CACTGGGGTTACTGGTGGCCATGAAGGAGTCCCTGCTGCTGTCAGAACAGAAGACCTCGCTGCCCTGAGGAC
AAGCACTTGCCACCACCGTCACTCAGCCCTGGGCGTAGCCGGACAGGAGGAGAGCAGTGATGCGGATGGGT
ACCCGGGCACACCAGCCCTCAGAGACCTGAGCTCTTCTGGCCACGTGGAACCTCGAACCCGAGCTCCTGCAGA
AGTGGCCCTGGAGATTGAGGGTCCCTGGACACTCCCTATGGAGATCCGGGGAGCTAGGATGGGGAACCTGC
CACAGCCAGAACTGAGGGGCTGGCCCCAGGCAGCTCCCAGGGGGTAGAACGGCCCTGTGCTTAAGACACTCC
TGCTGCCCCGTCTGAGGGTGGCAATTAAAGTTGCTTCACATCCTC (SEQ ID NO. 937)

[0074] A protein sequence from CD320 derived from the DNA
sequence above is as follows:
>sp I Q9NPF0-2ICD320_HU MAN Isoform 2 of CD320 antigen OS=Homo sapiens OX=9606 GN=CD320 MSGGWMAQVGAWRTGALGLALLLLLGLG LG LEAAASPLSTPTSAQAAG I EPCTQKGQCPP PPG
LPCPCTGVSDC
SGGTDKKLRNCSR LACLAGELRCTLSDDCI PLTWRCDG HP DCP DSSD ELGCGTN El LP EG
DATTMGPPVTLESVTSL
RNATTM G P PVTLESVPSVG NATSSSAG DQSGSPTAYGVIAAAAVLSASLVTATLLLLSWLRAQE R LRP
LGLLVAM K
ESLLLSEQKTSLP (SEQ ID NO. 938)

[0075] Further, as used herein, "LRP2" refers to the gene or protein. LRP2 is also known as nnegalin, LRP-2, Glycoprotein 330, DBS, GP330, Gp330, Calcium Sensor Protein, Heymann Nephritis Antigen Honnolog, Low-Density Lipoprotein Receptor-Related Protein 2, EC
1.1.2.3, EC 3.4.21.9, LDL
receptor related protein 2. The term LRP2 includes human LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No.
NM_004525.3; mouse LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_001081088.2; rat LRP2, the amino acid and nudeotide sequence of which may be found in, for example, GenBank Accession No. NM_030827.1. Additional examples of LRP2 mRNA
sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 18.

[0076] One example of LRP2 is: >NM_004525.3 Homo sapiens LDL
receptor related protein 2 (LRP2), DNA:
GGTCTAAAGGGCTITATGCACTGTCTGGAGGGTGGGGACTGGCGCGGGTAGAAAACGGGATGCCTCGGGC
GTGGGGGCAGGCTITTGGCCACTAGGAGCTGGCGGAGGTGCAGACCTAAAGGAGCGTTCGCTAGCAGAGG
CGCTGCCGGTGCGGTGTGCTACGCGCGCCCACCTCCCGGGGAAGGAACGGCGAGGCCGGGGACCGTCGCG
GAGATGGATCGCGGGCCGGCAGCAGTGGCGTGCACGCTGCTCCTGGCTCTCGTCGCCTGCCTAGCGCCGG
CCAGTGGCCAAGAATGTGACAGTGCGCATTTTCGCTGTGGAAGTGGGCATTGCATCCCTGCAGACTGGAG
GTGTGATGGGACCAAAGACTGTTCAGATGACGCGGATGAAATTGGCTGCGCTGTTGTGACCTGCCAGCAG
GGCTATTTCAAGTGCCAGAGTGAGGGACAATGCATCCCCAACTCCTGGGTGTGTGACCAAGATCAAGACT
GTGATGATGGCTCAGATGAACGTCAAGATTGCTCACAAAGTACATGCTCAAGTCATCAGATAACATGCTC
CAATGGTCAGTGTATCCCAAGTGAATACAGGTGCGACCACGTCAGAGACTGCCCCGATGGAGCTGATGAG
AATGACTGCCAGTACCCAACATGTGAGCAGCTTACTTGTGACAATGGGGCCTGCTATAACACCAGTCAGA
AGTGTGATTGGAAAGTTGATTGCAGGGACTCCTCAGATGAAATCAACTGCACTGAGATATGCTTGCACAA
TGAGTITTCATGTGGCAATGGAGAGTGTATCCCTCGTGCTTATGTCTGTGACCATGACAATGATTGCCAA
GACGGCAGTGACGAACATGCTTGCAACTATCCGACCTGCGGTGGTTACCAGTTCACTTGCCCCAGTGGCC
GATGCATTTATCAAAACTGGGTTTGTGATGGAGAAGATGACTGTAAAGATAATGGAGATGAAGATGGATG
TGAAAGCGGTCCTCATGATGTTCATAAATGTTCCCCAAGAGAATGGTCTTGCCCAGAGTCGGGACGATGC
ATCTCCATTTATAAAGTTTGTGATGGGATTTTAGATTGCCCAGGAAGAGAAGATGAAAACAACACTAGTA
CCGGAAAATACTGTAGTATGACTCTGTGCTCTGCCTTGAACTGCCAGTACCAGTGCCATGAGACGCCGTA
TGGAGGAGCGTGITTTTGTCCCCCAGGTTATATCATCAACCACAATGACAGCCGTACCTGTGTTGAGTTT
GATGATTGCCAGATATGGGGAATTTGTGACCAGAAGTGTGAAAGCCGACCTGGCCGTCACCTGTGCCACT
GTGAAGAAGGGTATATCTTGGAGCGTGGACAGTATTGCAAAGCTAATGATTCCTTTGGCGAGGCCTCCAT
TATCTTCTCCAATGGTCGGGATTTGTTAATTGGTGATATTCATGGAAGGAGCTTCCGGATCCTAGTGGAG
TCTCAGAATCGTGGAGTGGCCGTGGGTGTGGCTITCCACTATCACCTGCAAAGAGTTITTTGGACAGACA
CCGTGCAAAATAAGGTTITTTCAGTTGACATTAATGGTTTAAATATCCAAGAGGTTCTCAATGTTTCTGT

TG AAACCCCAG AG AACCTG G CTGTG G ACTGG GTTAATAATAAAATCTATCTAGTGGAAACCAAG
GTCAAC
CG CATAGATATG GTAAATTTG GATGG AA G CTATCG GGTTACCCTTATAACTGAAAACTTGG G
GCATCCTA
G AG G AATTGCCGTGG AC CCAACTG TTG G TTATTTATTTTICTCAG ATTG GG AG AG CCTTTCTGGG
GAACC
TAAG CTGG AAA G G GCATTCATGGATGG CA G CAACCG TAAAG ACTTG GTGAAAACAAAG CTG G
GATGG CCT
G CTGG GGTAACTCTG GATATGATATCG AAG CGTG TTTA CTG G G TTG A CTCTCG G TTTG
ATTACATTG AAA
CTGTAACTTATGATGGAATTCAAAG G AAG ACTG TAG TTCATG GAG G CTCCCTCATTCCTCATCCCTTTGG

AG TAAG CTTATTTG AAG G TCA G G TG TTCTTTA CAG ATTG G ACAAAG ATG GC C GTG CTG
AA G G CAAACAAG
TTCACA G AG AC CAA CCCACAAG TG TA CTACCAG G CTTCC CTG A G G CC CTATG G AG TG
ACTGTTTACCATT
CC CTCAGACAG CCCTATG CTACCAATCCGTGTAAAGATAACAATGGGGGCTGTGAGCAG GTCTGTGTCCT
CA G C CACAG AACAGATAATGATG GTTTG GGTTTCCGTTGCAAGTG CACATTCG GCTTCCAACTG
GATACA
G ATG AG CG CCACTGCATTGCTGTTCAG AATTTCCTCATTITTTCATC CCAAG TTG CTATTCG TG G G
ATCC
CGTTCACCTTGTCTACCCAGG AA G ATGTCATG GTTCCAGTTTCG GG GAATCCTTCTITCTTTGTCGG GAT
TGATTTTGACGCCCAG GACAG CACTATC ______________ II 11111 CAGATATGTCAAAACACATGATTTTTAAG CAAAAG
ATTGATGG CACAG G AA G A GAAATTCTCG CAG CTAACAGGGTG G AAAATGTTG AAAG TTTG
GCTTTTGATT
G GATTTCAAAGAATCTCTATTG G A CAG ACTCTCATTACAAG AG TATCAG TGTCATG AG GCTAG
CTGATAA
AA CG AG A CG CACAG TA GTTCAG TATTTAAATAA CC CACG G TC G G TG GTAG TTCATC
CTTTTG CCG G G TAT
CTATTCTTCACTGATTG GTTCCGTCCTGCTAAAATTATG AG AG CATG G A GTG AC G G
ATCTCACCTCTTGC
CTGTAATAAACACTACTCTTGGATG GCCCAATGG CTTG GC CATC G ATTG G G CTG CTTCAC G ATTG
TA CTG
G GTAGATG CCTATTTTG ATAAAATTG AG CACAG CAC CTTTG ATG GTTTAG ACA G AA G AAG
ACTG GG CCAT
ATAG AG CAG ATGACACATCCGTTTGG ACTTGCCATCTTTGG AG AG CATTTATTTTTTACTGACTG GAGAC

TG G GTGCCATTATTCG AGTCAGG AAA G CA G ATG GTGG AG AAATG ACAGTTATCCG AAGTG
GCATTG CTTA
CATACTGCATTTG AAATCGTATG ATG TCAA CATC CAG A CTG GTTCTAACG CCTGTAATCAACCCACG
CAT
CCTAACGGTGACTG CAG CCACTTCTGCTTCCCG GTG CCAAATTTCCAG CG AG TG TG TG G
GTGCCCTTATG
G AATG AG G CTGGCTTCCAATCACTTGACATG CG AG GG G GACCCAACCAATG AACCACCCACAG AG
CAG TG
TG G CTTATTTTCCTTCCCCTGTAAAAATG GCAG ATGTGTG CC CAATTACTATCTCTG TG ATG G AG
TCG AT
G ATTG TCATG ATAACAGTGATG AG CAACTATGTGG CACACTTAATAATACCTGTTCATCTTCG GCGTTCA
CCTGTGGCCATG GGG AG TG CATTC CTG CA CACTG GCG CTGTG ACAAACGCAACG A CTGTGTG G
ATG GCAG
TG ATG AG CACAACTG CCCCACCCACG CACCTG CTTCCTG CCTTG ACACCCAATACACCTGTG
ATAATCAC
CA GTG TATCTCAAA G AA CTG G GTCTGTG A CACAG A CAATG ATTG TGG
GGATGGATCTGATGAAAAGAACT
G CAATTCG ACA G A G ACATG C CAA CCTAG TCAG TTTAATTG CCCCAATCATCGATGTATTG AC
CTATCGTT
TGTCTGTGATGGTGACAAGGATTGTGTTGATG GATCTG ATG AG GTTG GTTG TG TATTAAACTG TACTG
CT
TCTCAATTCAAGTGTG CCAGTGG GGATAAATGTATTG GCGTCACAAATCGTTGTGATG G TG TTTTTG ATT
G CAGTGACAACTCG GATGAAG CAG G CTG TC CAAC CA G G C CTCCTG GTATGTG
CCACTCAGATGAATTTCA
GTG CCAAGAAGATG GTATCTG CATC CC G AACTTCTG G GAATGTGATGGG CATCCAG
ACTGCCTCTATGG A

TCTGATGAGCACAATGCCTGTGTCCCCAAGACTTGCCCTTCATCATATTTCCACTGTGACAACGGAAACT
GCATCCACAGGGCATGGCTCTGTGATCGGGACAATGACTGCGGGGATATGAGTGATGAGAAGGACTGCCC
TACTCAGCCCTTTCGCTGTCCTAGTTG GCAATGG CAGTGTCTTG GCCATAACATCTGTGTGAATCTGAGT
GTAGTGTGTGATGG CATCTTTGACTG CCCCAATG G GACAGATGAGTCCCCACTTTGCAATG GGAACAG CT
GCTCAGATTTCAATGGTGGTTGTACTCACGAGTGTGTTCAAGAGCCCTTTGGGGCTAAATGCCTATGTCC
ATTGGGATTCTTACTTGCCAATGATTCTAAGACCTGTGAAGACATAGATGAATGTGATATTCTAGGCTCT
TGTAGCCAGCACTGTTACAATATGAGAGGTTCTTTCCGGTGCTCGTGTGATACAGGCTACATGTTAGAAA
GTGATGG GAG GACTTG CAAAGTTACAG CATCTGAGAGTCTG CTGTTACTTGTG GCAAGTCAGAACAAAAT
TATTGCCGACAGTGTCACCTCCCAGGTCCACAATATCTATTCATTGGTCGAGAATGGTTCTTACATTGTA
GCTGTTGATTTTGATTCAATTAGTGGTCGTATCTITTGGTCTGATGCAACTCAGGGTAAAACCTGGAGTG
CGTTTCAAAATG GAACG GACAGAAGAGTGGTATTTGACAGTAGCATCATCTTGACTGAAACTATTG CAAT
AGATTG GGTAG GTCGTAATCTTTACTG GACAGACTATG CTCTG GAAACAATTGAAGTCTCCAAAATTGAT
GGGAGCCACAGGACTGTGCTGATTAGTAAAAACCTAACAAATCCAAGAGGACTAGCATTAGATCCCAGAA
TGAATGAGCATCTACTGTTCTGGTCTGACTGGGGCCACCACCCTCGCATCGAGCGAGCCAGCATGGACGG
CAGCATGCGCACTGTCATTGTCCAGGACAAGATCTTCTGGCCCTGCGGCTTAACTATTGACTACCCCAAC
AGACTGCTCTACTTCATGGACTCCTATCTTGATTACATGGACTTTTGTGATTATAATGGACACCATCGGA
GACAGGTGATAGCCAGTGATTTGATTATACGGCACCCCTATGCCCTAACTCTCTTTGAAGACTCTGTGTA
CTGGACTGACCGTGCTACTCGTCGGGTTATGCGAGCCAACAAGTGGCATGGAGGGAACCAGTCAGTTGTA
ATGTATAATATTCAATGGCCCCTTGGGATTGTTGCGGTTCATCCTTCGAAACAACCAAATTCCGTGAATC
CATGTGCCTTITCCCGCTGCAGCCATCTCTGCCTGCTITCCTCACAGGGGCCTCATTITTACTCCTGTGT
TTGTCCTTCAGGATGGAGTCTGTCTCCTGATCTCCTGAATTGCTTGAGAGATGATCAACCTITCTTAATA
ACTGTAAGGCAACATATAATTTTTGGAATCTCCCTTAATCCTGAGGTGAAGAGCAATGATGCTATGGTCC
CCATAGCAGGGATACAGAATGGTTTAGATGTTGAATTTGATGATGCTGAGCAATACATCTATTGGGTTGA
AAATCCAG GTGAAATTCACAGAGTGAAGACAGATGGCACCAACAG GACAGTATTTG CTTCTATATCTATG
GTGGGGCCTTCTATGAACCTGGCCTTAGATTGGATTTCAAGAAACCITTATTCTACCAATCCTAGAACTC
AGTCAATCGAG GTTTTGACACTCCACG GAGATATCAGATACAGAAAAACATTGATTG CCAATGATG GGAC
AG CTCTTG GAGTTG GCTTTCCAATTGG CATAACTGTTGATCCTG CTCGTG GGAAG CTGTACTGGTCAGAC
CAAGGAACTGACAGTGGGGTTCCTGCCAAGATCGCCAGTGCTAACATGGATGGCACATCTGTGAAAACTC
TCTTTACTGG GAACCTCGAACACCTG GAGTGTGTCACTCTTGACATCGAAGAG CAGAAACTCTACTGGG C
AGTCACTGGAAGAGGAGTGATTGAAAGAGGAAACGTGGATGGAACAGATCGAATGATCCTGGTACACCAG
CTTTCCCACCCCTGGGGAATTGCAGTCCATGATTCTTTCCTTTATTATACTGATGAACAGTATGAGGTCA
TTGAAAGAGTTGATAAGGCCACTGGGGCCAACAAAATAGTCTTGAGAGATAATGTTCCAAATCTGAGGGG
TCTTCAAGTTTATCACAGACGCAATGCCGCCGAATCCTCAAATGGCTGTAGCAACAACATGAATGCCTGT
CAGCAGATTTGCCTGCCTGTACCAGGAGGATTGTITTCCTGCGCCTGTGCCACTGGATTTAAACTCAATC

CTGATAATCGGTCCTG CTCTCCATATAACTCTTTCATTGTTGTTTCAATG CTGTCTG CAATCA GA G GCTT
TA G CTTG G AATTGTCAGATCATTCAGAAACCATG GTGCCGGTGG CA G GC CAAG G A CG AAA CG
CACTG CAT
GTG GATGTGGATGTGTCCTCTGG CTTTATTTATTG GTGTGATTTTAGCAG CTCAGTG G CATCTGATAATG
CGATCCGTAGAATTAAACCAGATGGATCTTCTCTGATGAACATTGTGACACATG GAATAG G AG AAAATG G
AG TC CG GG GTATTGCAGTGGATTGG GTAGCAG GAAATCTTTATTTCACCAATG CCTTTGTTTCTGAAACA
CTGATAGAAGTTCTG CGGATCAATACTACTTACCG CCGTGTTCTTCTTAAAGTCACAGTGGACATG CCTA
G GCATATTGTTGTAGATCCCAAGAACAGATACCTCTTCTG G G CTG A CTATG GG CA G A G ACCAAAG
ATTG A
G CGTTCTTTCCTTG ACTGTACCAATCG AACAGTGCTTGTGTCAG AG G G CATTGTCACACCACG GG G
CTTG
G CAGTGG ACC G AAGTG ATG G CTACGTTTATTG GGTTGATGATTCTTTAGATATAATTGCAAGGATTCGTA

TCAATG G A G AG AA CTCTG AAGTGATTCGTTATGG CAGT CG TTAC C CAA CTC CTTATG G
CATCACTGTTTT
TGAAAATTCTATCATATGG GTAGATAG GAATTTGAAAAAGATCTTCCAAG CCAG CAA GG AA CCA G AG
AA C
ACAG AG CCACCCACAGTGATAAG AG ACAATATCAACTGGCTAAGAG ATGTGACCATCTTTG ACAAGCAAG
TC CAG C CC CG G TCAC CAG CAG AG GTCAACAACAACCCTTGCTTG GAAAACAATGGTG GGTG
CTCTCATCT
CTG CTTTG CTCTGCCTG GATTG CA CAC CC CAAAATGTG ACTGTG CCTTTGGG A CC CTG
CAAAGTGATG GC
AA G AATTG TG CCATTTCAA CA G AAAATTTCCTCATCTTTG C CTTGTCTAATTCCTTG AG AAG
CTTACACT
TG G AC CCTG AAAA CCATAG C CCA CCTTTC CAAACAATAAATG TG GAAAG AACTG TCATG
TCTCTAG ACTA
TGACAGTGTAAGTGATAGAATCTACTTCACACAAAATTTAG C CTCTG G A GTTG GACAGATTTCCTATG CC
AC CCTG TCTTCAG GGATCCATACTCCAACTGTCATTG CTTCAG GTATAG GGACTG CTGATG GCATTG
CCT
TTGACTGGATTACTAGAAGAATTTATTACAGTGACTACCTCAACCAGATGATTAATTCCATG GCTG AAG A
TG G GTCTAACCGCACTGTGATAG CCCG CGTTCCAAAACCAAG AG CAATTGTGTTAGATCCCTG CCAAG GG

TA CCTG TACTG G GCTGACTGGG ATACACATGCCAAAATCGAGAG AG CCACATTG G
GAGGAAACTTCCGCG
TA CC CATTG TG AA CAG CA GTCTG G TCATG CCCAGTG GG CTG A CTCTG G ACTATG AAG AG
G AC CTTCTCTA
CTG GGTGG ATG CTAG TCTG CAG A G G ATTG AACG CAG CACTCTG ACG GG CG TG G ATCGTG
AA G TCATTG TC
AATG CAG CCGTTCATGCTTTTG GCTTGACTCTCTATGG C CA GTATATTTACTG GACTG ACTTG TA
CACAC
AAAG AATTTACC G A G CTAACAAATATG AC G G GTCAGGTCAG ATTG CAATG AC CACAAATTTG
CTCTCCCA
G CCCAG GG GAATCAACACTGTTGTG AAG AAC CA G AAACAACAG TG TAACAATCCTTGTG AA CAG
TTTAAT
GGGGG CTGCAG CCATATCTGTG CAC CAG GTCCAAATG GTG CCG AG TG CCAGTGTCCACATG AG GG
CAA CT
G GTATTTGG CCAACAACA G G AA G CACTG CATTGTG GACAATG GTGAACGATGTGGTG
CATCTTCCTTCAC
CTG CTCCAATG GG CG CTG CATCTCG GAAG AGTGG AAG TGT GATAATG A CAAC G ACTG TG G
GGATG GCAGT
G ATG AG ATGG AAA GTG TCTGTG CACTTCACACCTGCTCACCGACAGCCTTCACCTGTG CCAATG GG CG
AT
GTGTCCAATACTCTTACCG CTGTGATTACTACAATGACTGTG GTGATG GCAGTG ATG AG G CA G GGTG
CCT
GTTCAG G GACTGCAATGCCACCACGGAGTTTATGTGCAATAACAGAAGGTGCATACCTCGTGAGTTTATC
TG CAATG G TG TAG ACAACTG CCATGATAATAACACTTCAG ATG AG AAAAATTG CC CTG ATC G CA
CTTG C C
AG TCTG GATACACAAAATGTCATAATTCAAATATTTGTATTCCTCG CGTTTATTTGTGTG AC G G A GA
CAA

TGACTGTG G A G ATAACAGTG ATG AAAA CCCTA CTTATTG CACCACTCACAC G TG CAG CAG CA G
TG A G TTC
CAATG CGCATCTGG G CGCTGTATTCCTCAACATTG GTATTG TG ATCAAG AAACAG ATTG TTTTG ATG
C CT
CTG ATG AA CCTG CCTCTTGTG GTCA CTCTG A G CGAACATG CCTAGCTG ATG AG TTCAAGTG TG
ATGGTG G
G AG G TG CATCC CAAG C G AATG G ATCTGTG A C G GTG ATAATG A CTGTG G GG ATATG A
GTG AC G AG G ATAAA
AG GCACCAGTGTCAGAATCAAAACTGCTCGG ATTCCG AGTTTCTCTGTGTAAATGACAGACCTCCGG ACA
G GAG GTGCATTCCCCAGTCTTGG GTCTGTGATG GCGATGTG GATTGTACTGACG G CTA CG ATG A G
AATCA
GAATTG CA CCA G G AG AACTTGCTCTG AAAATG AATTCACCTGTG
GTTACGGACTGTGTATCCCAAAGATA
TTCAGGTGTG AC CG G CA CAATG A CTG TG GTGACTATAG CG ACG AG AG G GG
CTGCTTATACCAGACTTGCC
AA CAG AATCAGTTTACCTGTCAG AA CG G G CGCTG CATTAG TAAAAC CTTCGTCTGTG ATG A G G
ATAATG A
CTGTG G A G ACG G ATCTG ATG A G CTGATG CAC CTG TG CCACAC CC CAG AAC CCAC
GTGTCCACCTCAC G AG
TTCAAG TGTG A CAATG G G CGCTG CATC G AG ATGATGAAACTCTG CAAC CA CCTA G ATG ACTG
TTTG GACA
ACAG CG ATG AG AAAGG CTGTG GCATTAATGAATG CCAT GA CC CTTCAATCAG TG GCTG
CGATCACAACTG
CA CAG ACACCTTAACCAGTTICTATTGTTCCTGTCGTCCTG GTTACAAG CTCATGTCTGACAAGCG GACT
TGTGTTGATATTG ATG AATG CACA G A G ATG CCTTTTGTCTGTAG CCAG AAGTGTG AG
AATGTAATAGG CT
CCTACATCTGTAAGTGTG CCC CA G G CTA CCTCCG A G AACCAG ATG G AAAG AC CTG CC G G
CAAAACAGTAA
CATCGAACCCTATCTCATTTTTAGCAACCGTTACTATTTGAG AAATTTAACTATAG ATGGCTATTTTTAC
TCCCTCATCTTGGAAG G A CTG GACAATGTTGTG G CATTAG ATTTTG ACC G AGTAG AG AAG AG
ATTGTATT
G GATTGATACACAG AG GCAAGTCATTGAGAGAATGTTTCTGAATAAG ACAAACAAGG AG ACAATCATAAA
CCACAGACTACCAG CTG CAG AAA GTCTG G CTG TAG ACTG GGTTTCCAGAAAG CTCTACTGGTTGGATG
CC
CG CCTG GATG G CCTCTTTG TCTCTG A CCTCAATG GTGGACACCG CC G CATG CTGG CCCAG CA
CTG TG TG G
ATGCCAACAACACCTTCTG CTTTGATAATCCCAG AG G ACTTG C CCTTCAC CCTC AATATG G G TA
CCTCTA
CTG GG CAGACTGG GGTCACCG CGCATACATTGG GAGAGTAGG CATG GATGG AAC CAA CAAG TCTGTG
ATA
ATCTCCACCAAGTTAG AG TG G CCTAATG G CATCACCATTG ATTA CAC CAATG ATCTA CTCTACTG G
G CA G
ATGCCCACCTGGGTTACATAG AG TACTCTG ATTTG GAG G GCCACCATCGACACACGGTGTATGATGGGGC
ACTG CCTCACCCTTTCG CTATTACCATTTTTGAAG ACACTATTTATTGG ACAG ATTGG AATACAAGG ACA
GTG GAAAAG GG AAACAAATATG ATGG ATCAAATA G ACAG A CACTG GTG AACA CAA CACACAG A
CCATTTG
ACATC CATG TG TA CCATCCATATAG G CAGCCCATTGTG AG CAATCC CTGTG G TA CCAACAATG
GTG G CTG
TTCTCATCTCTGCCTCATCAAG CCAGG AG GAAAAG GGTTCACTTG CG AGTGTCCAG ATG ACTTCC G
CAC C
CTTCAG CTG A GTG G CAG CACCTACTGCATG CCCATGTG CTC CA G CACC CA GTTCCTG TG C G
CTAACAATG
AAAAGTG CATTCCTATCTG GTG GAAATGTGATG G ACA G AAA G A CTG CTCAGATG G
CTCTGATGAACTGG C
CCTTTG CCCG CAG CG CTTCTG CCGACTGG G ACAGTTCCAG TGCA GTG ACG G CAA CTG CAC CAG
CC CG CA G
ACTTTATGCAATG CTCACCAAAATTG CC CTG ATG G GTCTGATGAAG ACC GTCTTCTTTGTG AG
AATCAC C
ACTGTGACTCCAATGAATGG CAG TG C G C CAA CAAACGTTG CATCC CA G AATCCTG G
CAGTGTGACACATT
TAACG A CTG TG AG GATAACTCAG ATG AAG ACAGTTCC CA CTGTG C CA G CA G G ACCTG CC
G G CC G G G CCAG

TTTCGGTGTGCTAATGGCCGCTGCATCCCGCAGGCCTGGAAGTGTGATGTGGATAATGATTGTGGAGACC
ACTCGGATGAGCCCATTGAAGAATGCATGAGCTCTGCCCATCTCTGTGACAACTTCACAGAATTCAGCTG
CAAAACAAATTACCGCTGCATCCCAAAGTGGGCCGTGTGCAATGGTGTAGATGACTGCAGGGACAACAGT
GATGAG CAAGGCTGTGAGGAGAGGACATGCCATCCTGTGGGGGATTTCCGCTGTAAAAATCACCACTG CA
TCCCTCTTCGTTGGCAGTGTGATGGGCAAAATGACTGTGGAGATAACTCAGATGAGGAAAACTGTGCTCC
CCGGGAGTGCACAGAGAGCGAGTTTCGATGTGTCAATCAGCAGTGCATTCCCTCGCGATGGATCTGTGAC
CATTACAACGACTGTGGGGACAACTCAGATGAACGGGACTGTGAGATGAGGACCTGCCATCCTGAATATT
TTCAGTGTACAAGTGGACATTGTGTACACAGTGAACTGAAATGCGATGGATCCGCTGACTGTTTGGATGC
GTCTGATGAAGCTGATTGTCCCACACGCTTTCCTGATGGTGCATACTGCCAGGCTACTATGTTCGAATGC
AAAAACCATGTTTGTATCCCGCCATATTGGAAATGTGATGGCGATGATGACTGTGGCGATGGTTCAGATG
AAGAACTTCACCTGTGCTTGGATGTTCCCTGTAATTCACCAAACCGTTTCCGGTGTGACAACAATCGCTG
CATTTATAGTCATGAG GTGTG CAATGGTGTGGATGACTGTG GAGATG GAACTGATGAGACAGAGGAG CAC
TGTAGAAAACCGACCCCTAAACCTTGTACAGAATATGAATATAAGTGTGGCAATGGGCATTGCATTCCAC
ATGACAATGTGTGTGATGATGCCGATGACTGTGGTGACTGGTCCGATGAACTGGGTTGCAATAAAGGAAA
AGAAAGAACATGTGCTGAAAATATATGCGAGCAAAATTGTACCCAATTAAATGAAGGAGGATTTATCTGC
TCCTGTACAGCTGGGTTCGAAACCAATGTITTTGACAGAACCTCCTGTCTAGATATCAATGAATGTGAAC
AATTTGGGACTTGTCCCCAGCACTGCAGAAATACCAAAGGAAGTTATGAGTGTGTCTGTGCTGATGGCTT
CACGTCTATGAGTGACCG CCCTG GAAAACGATGTG CAG CTGAG G GTAGCTCTCCTTTGTTG CTACTGCCT
GACAATGTCCGAATTCGAAAATATAATCTCTCATCTGAGAGGTTCTCAGAGTATCTTCAAGATGAGGAAT
ATATCCAAGCTGTTGATTATGATTGGGATCCCAAGGACATAGGCCTCAGTGTTGTGTATTACACTGTGCG
AGGGGAGGGCTCTAG GTTTGGTG CTATCAAACGTGCCTACATCCCCAACTTTGAATCCGGCCG CAATAAT
CTTGTGCAGGAAGTTGACCTGAAACTGAAATACGTAATGCAGCCAGATGGAATAGCAGTGGACTGGGTTG
GAAGGCATATTTACTGGTCAGATGTCAAGAATAAACGCATTGAGGTGGCTAAACTTGATGGAAGGTACAG
AAAGTGGCTGATTTCCACTGACCTGGACCAACCAGCTGCTATTGCTGTGAATCCCAAACTAGGGCTTATG
TTCTGGACTGACTGGGGAAAGGAACCTAAAATCGAGTCTGCCTGGATGAATGGAGAGGACCGCAACATCC
TGGTITTCGAGGACCTTGGTTGGCCAACTGGCCITTCTATCGATTATTTGAACAATGACCGAATCTACTG
GAGTGACTTCAAG GAG GACGTTATTGAAACCATAAAATATGATGG GACTGATAGGAGAGTCATTG CAAAG
GAAGCAATGAACCCTTACAGCCTGGACATCTTTGAAGACCAGTTATACTGGATATCTAAGGAAAAGGGAG
AAGTATGGAAACAAAATAAATTTGGGCAAGGAAAGAAAGAGAAAACGCTGGTAGTGAACCCTTGGCTCAC
TCAAGTTCGAATCTITCATCAACTCAGATACAATAAGTCAGTGCCCAACCITTGCAAACAGATCTGCAGC
CACCTCTGCCTTCTGAGACCTGGAGGATACAGCTGTGCCTGTCCCCAAGGCTCCAGCTITATAGAGGGGA
GCACCACTGAGTGTGATGCAGCCATCGAACTGCCTATCAACCTGCCCCCCCCATGCAGGTGCATGCACGG
AG GAAATTGCTATTTTGATGAGACTGACCTCCCCAAATGCAAGTGTCCTAGCGG CTACACCGGAAAATAT
TGTGAAATGGCGTTTTCAAAAGG CATCTCTCCAG GAACAACCGCAGTAG CTGTGCTGTTGACAATCCTCT

TG ATCGTCGTAATTG GAG CTCTGG CAATTG CAG GATTCTTCCACTATAGAAG GACCGG CTCCCTTTTGCC

TGCTCTGCCCAAGCTGCCAAGCTTAAGCAGTCTCGTCAAGCCCTCTGAAAATGGGAATGGGGTGACCTTC
AG ATCAG GG G CAG ATCTTAACATGG ATATTGGAGTGTCTG GTTTTGG ACCTG
AGACTGCTATTGACAGGT
CAATGGCAATGAGTGAAGACTTTGTCATGGAAATGGGGAAGCAGCCCATAATATTTGAAAACCCAATGTA
CTCAGCCAG AG ACAGTGCTGTCAAAGTG GTTCAGCCAATCCAG GTGACTGTATCTGAAAATGTG GATAAT
AAGAATTATGGAAGTCCCATAAACCCTTCTGAGATAGTTCCAGAGACAAACCCAACTTCACCAGCTGCTG
ATGGAACTCAGGTGACAAAATGGAATCTCTTCAAACGAAAATCTAAACAAACTACCAACTTTGAAAATCC
AATCTATG CACAGATGG AGAACG AG CAAAAG G AAAGTGTTGCTG CGACACCACCTCCATCACCTTCG CTC

CCTGCTAAGCCTAAGCCTCCTTCG AG AAG AGACCCAACTCCAACCTATTCTG CAACAGAAG ACACTTTTA
AAGACACCGCAAATCTTGTTAAAGAAGACTCTGAAGTATAGCTATACCAGCTATTTAGGGAATAATTAGA
AACACACTTTTGCACATATATTTTTTACAAACAGATGAAAAAAGTTAACATTCAGTACTTTATGAAAAAA
ATATATTMCCCTGITTGCCTATAGTTGGAGGTATCCTGTGTGR. __________ IIIIIII
ACTTATGCCGTCTCATA
TTTTTACAAATAATTATCACAATGTACTATATGTATATCTTTGCACTGAAGTTGTCTGAAGGTAATACTA
TAAATATATTGTATATTTGTAAATTTTGGAAAGATTATCCTGTTACTGAATTTGCTAATAAAGATGTCTG
CTGATTTG GTTG GTGATCATTATAGTAAATGATCCAACAAGAAAAG GAATTGACTGG GG AC CTTTAG CCG
TGTCTAAAGAAGAGGCACCACTCATATTTCCTATAAAATTATCTAGGAAAGGAATCCAGGCCCCGCTCTT
GGGTCCATTTTTACACATTAGCACTTAATTAATGTTCAATATTACATGTCAATTTGATTAATGGCTATGT
TG ATAG GG GCCACTATGTGTTGTATAG ACATCTG GACTTGACTGTAG ACTCCTCAGATAATACAG AAG GT

AG GAAAAGCAATTCAGTTTG GCCCTTCTGTGTGTTG GCATTGTCTAACCAG AACTCTCTGTTTCATGTGT
GTTCTCTCACTAGCTGCCAAGACAACATTTTTATTTGTGATGTCTATGAGGAAATCCCATATCATTAAGT
GCCAGTGTCCTGCATTGAGTTTGTGGTTAATTAAATGAGCTCTTCTGCTGATGGACCCTGGAGCAATTTC
TCCCCTCACCTGACATTCAAGGTG GTCACCTG CCCTAGTAGTTG GAG CTCAGTAGCTGAATTTCTGAAAC
CAAATCTGTGTCTTCATAAAATAAGGTGCAAAAAAAAAAAATACCAGTTAAGTAAAGCCTCAACTGGGTT
TTTGTTTCTATGAAAATATCATTATAATCACTATTTATTTCCTAAGTTGAACCTGAATAGAAAGGGAAAC
CATTCTTATTAAGL ___________ 11111 ATTAGGCCCTGTGGCTAAATGTGTACATTTATATTAG
AATGTACTG TACAG
TCCAGATCTITTCTTTAATTCTTATTGG _________ 1111111111111111111111 AGAGATGGAGTCTTGCTATA
TTGCCAAGGCTGATCTTGAAGTCCTGGGCTCAAGTGATCCTCCCACCTCAGCCTCCTGAGTGGTTGGGGT
TACG G GCGTG AG CCACTGTGCCTGG CTTCCAG CTCTCCTCTTAAATAGTG GGTATAGTCTGCACAACAG G

AACCATGGCAGGAATATACACTTTCCCATAGCAAATAGCATACCTGACTCTCTGTGCTAATATTGCACAT
TTGTTAAACAATGAATGAATGGATGGATGGATGGATGGATGAATGAATGAAACATATACTACTGATTATT
TTATTCCAGAGTTCTCAAAATATTTGTTGCTGATATTTTGAGTGCTGACTGTAATTACTTTGATTAGATA
AACAACTGGAAATAATGCTGCTGAAAAAGTTCTAATAAATGTGTATTTTATCAGA (SEQ ID NO. 939).

[0077] One example of a protein sequence from the above LRP2 DNA is:
>spIP98164ILRP2_HUMAN Low-density lipoprotein receptor-related protein 2 OS=Honno sapiens OX=9606 GN=LRP2 PE=1 SV=3 MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEI
GCAVVICQQGYFKCCISEGQCIPNSWVCDQDQDCDDGSDERQDCSCISTCSSHOITCSNGQC
IPSEYRCDHVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCT
EICLHNEFSCGNGECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWV
CDGEDDCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENN
TSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDSRTCVEFDDCQIWGICDQ
KCESRPGRHLCHCEEGYILERGQYCKANDSFGEASIIFSNGRDLLIGDIHGRSFRILVES
QNRGVAVGVAFHYHLQRVFWTDTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNK
IYLVETKVNRIDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLER
AFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDGIQRKTVVHGGSL
IPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQASLRPYGVTVYHSLRQPYAT
NPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIR
GIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAA
NRVENVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTVVQYLNNPRSVVVHPFAGYL
FFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEHSTFD
GLDRRRLGHIEQMTHPFGLAIFGEHLFFTDWRLGAIIRVRKADGGEMTVIRSGIAYILHL
KSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNE
PPTEQCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGECI
PAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDE
KNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKC
IGVTNRCDGVFDCSDNSDEAGCPTRPPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGS
DEHNACVPKTCPSSYFHCDNGNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCL
GHNICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFL
LANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYMLESDGRTCKVTASESLLLLV
ASQNKIIADSVTSQVHNIYSLVENGSYIVAVDFDSISGRIFWSDATQGKTWSAFQNGTDR
RVVFDSSIILTETIAIDWVGRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALD
PRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDSYLD
YMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRVMRANKWHGGNQSVVM
YNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCPSGWSLSPDLLNC

LRDDQPFLITVRQH I IFG ISLN PEVKSN DAMVPIAG IQN G LDVEFD DAEQYIYWVE N PG E
I H RVKTDGTN RTVFASISMVGPSM NLALDWISRN LYSTN PRTQSI EVLTLHGD I RYRKTL
IAN DGTALGVGFPIGITVD PARG KLYWSDQGTDSGVPAKIASAN M DGTSVKTLFTGN LEH
LECVTLDIEEQKLYWAVTG RGVI ERG NVDGTDRM I LVHQLSH PWG IAVH DSFLYYTDEQY
EVIERVDKATGANKIVLRDNVPN LRGLQVYH RRNAAESSNGCSNNM NACQQICLPVPGGL
FSCACATGFKLNPDNRSCSPYNSFIVVSM LSAIRGFSLELSDHSETMVPVAGQGRNALHV
DVDVSSGFIYWCDFSSSVASDNAIRRIKPDGSSLM NIVTHGIGENGVRGIAVDWVAGN LY
FTNAFVSETLIEVLRINTTYRRVLLKVTVDM PRH IVVDPKN RYLFWADYGQRPKI ERS FL
DCTN RTVLVSEG IVTPRGLAVDRSDGYVYWVDDSLD I IAR I RI NG E NSEVI RYGSRYPTP
YG ITVFENSIIWVDRN LKKI FQASKE PE NTE PPTVIRD N INWLRDVTIFDKQVQPRSPAE
VNNNPCLENNGGCSH LCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRS
LH LD PE N HSPPFQTI NVERTVMSLDYDSVSD RIYFTQN LASGVGQISYATLSSGIHTPTV
IASGIGTADGIAFDWITRRIYYSDYLNQM INSMAEDGSNRTVIARVPKPRAIVLDPCQGY
LYWADWDTHAKIERATLGGNFRVPIVNSSLVM PSG LTLDYE EDLLYWVDASLQRI E RSTL

NTVVKNQKQQCNNPCEQFNGGCSH ICAPGPNGAECQCPH EG NWYLAN N RKHCIVD NG E RC
GASSFTCSNGRCISEEWKCDNDNDCGDGSDEM ESVCALHTCSPTAFTCANGRCVQYSYRC
DYYN DCG DGS DEAGCLFR DCNATTEF MCN N RRCIPR EFICNGVD NCH DN NTSDEKNCPDR
TCQSGYTKCH NSN ICI PRVYLCDGDN DCGD NSDE N PTYCTTHTCSSS EFQCASG RCI PQH
WYCDCIETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDG DN DCGDMSDE D KR
HQCQNQNCSDSEFLCVN DRPPDRRCIPQSWVCDG DVDCTDGYD ENQNCTRRTCSE N E FTC
GYG LCIPKIFRCD RH N DCG DYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDG
SD ELM H LCHTPEPTCPPHEFKCDNGRCIEM MKLCN HLDDCLDNSDEKGCGIN ECH DPSIS
GCDHNCTDTLTSFYCSCRPGYKLMSDKRTCVDIDECTEM PFVCSQKCENVIGSYICKCAP
GYLRE PDG KTCRQNS N I EPYLI FSN RYYLRN LTIDGYFYSLI LEG LDNVVALDFD RVE KR
LYWIDTQRQVI ER M FLNKTNKETIIN HRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLN
GGH RRM LAQHCVDANNTFCFDNPRGLALH PQYGYLYWADWGH RAYIGRVGM DGTN KSVI I
STKLEWPNGITIDYTNDLLYWADAH LGYIEYSDLEGHH RHTVYDGALPH PFAITI FE DTI
YWTDWNTRTVE KG NKYDGSN RQTLVNTTH RPFDI HVYH PYRQPIVSN PCGTN NGGCSH LC
LI KPGG KG FTCECPD DFRTLQLSGSTYCM PMCSSTQFLCANNEKCIPIWWKCDGQKDCSD
GSDE LALCPQRFCRLGQFQCSDGNCTS PQTLCNAHCINCPDGSDE D MICE N H HCDSNEWQ
CANKRCI PESWQCDTFN DCEDNS DEDSSHCASRTCRPGQF RCANG RCIPQAWKCDVDN DC

GDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCH
PVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRWICDH
YNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGA
YCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCIYSH
EVCNGVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDEL
GCNKGKERTCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDIN ECEQFGTCPQH
CRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQD
EEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIKRAYIPNFESGRNN LVQEVDLKLKY
VMQPDGIAVDWVGRHIYWSDVKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMF
WTDWGKEPKIESAWMNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYD
GTDRRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKQNKFGQGKKEKTLVVNPWLTQVRI
FHQLRYNKSVPNLCKQICSHLCLLRPGGYSCACPQGSSFIEGSTTECDAAIELPINLPPP
CRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSKGISPGTTAVAVLLTILLIVVIGAL
AIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAI
DRSMAMSEDFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVIVSENVDNKNYGSPINPSE
IVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQKESVAATPPPSPSLP
AKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV (SEQ ID NO. 940).

[0078] As used herein, "target sequence" refers to a contiguous portion of the nucleotide sequence of an nnRNA molecule formed during the transcription of a gene of interest for example a CD320 gene or an LRP2 gene, including mRNA that is a product of RNA processing of a primary transcription product.

[0079] As used herein, the term "strand comprising a sequence" refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature.

[0080] "G," "C," "A" and "U" each generally stand for a nucleotide that contains guanine, cytosine, adenine, and uracil as a base, respectively. "T" and "dT" are used interchangeably herein and refer to a deoxyribonucleotide wherein the nucleobase is thynnine, e.g., deoxyribothymine, 2'-deoxythymidine or thymidine. However, it will be understood that the term "ribonucleotide" or "nucleotide" or "deoxyribonucleotide" can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nudeotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of the invention by a nucleotide containing, for example, inosine. Sequences comprising such replacement moieties are embodiments of the invention.

[0081] The term "siRNA" refers to a compound, cocktail, composition or agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA
hybridizes with its complementary mRNA molecule. The nnRNA is degraded by the RISC/AGO
complex, which has RNAse cleave activity, resulting in nnRNA degradation and the protein encoded by the nnRNA is not produced or is produced at a reduced level as compared to untreated cell. This causes the "knockdown" effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells. The siRNA modulates, e.g., inhibits, the expression of CD320 in a cell or LRP2 in a cell, e.g., a cell within a subject, such as a mammalian subject.

[0082] In one embodiment, an RNAi agent of the invention indudes a single stranded RNA
that interacts with a target RNA sequence, e.g., a CD320 or LRP2 target nnRNA
sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III
endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-Ill-like enzyme, processes the dsRNA into 19-23 base pair (bp) short interfering RNAs with characteristic two base 3 overhangs (Bernstein, et al., (2001) Nature 409:363). Initially, the siRNAs may consist of two RNA strands, an antisense (or guide) strand and a sense (or passenger) strand, which form a duplex that varies in length from 10-80 bp in length with or without a 3' nucleotide overhang. A
dsRNA can include one or more single-stranded overhang(s) of one or more nucleotides. In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, generally 1 or 2 nucleotides. In another embodiment, the antisense strand of the dsRNA has 1-10 nudeotide overhangs each at the 3' end and the 5' end over the sense strand. In further embodiments, the sense strand of the dsRNA
has 1-10 nucleotide overhangs each at the 3' end and the 5' end over the antisense strand.

[0083] The siRNA are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense (guide) strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target nnRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC
complex to effect silencing of the target gene, i.e., a CD320 or LRP2 gene.
Accordingly, the term "siRNA" is also used herein to refer to an RNAi as described above.

[0084] In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target nnRNA. Single-stranded RNAi agents bind to the RISC endonuclease Argonaute 2, which then cleaves the target nnRNA. The single-stranded siRNAs are generally 15-80 nucleotides and may be chemically modified to improve metabolic stability and activity; wherein one or multiple pyrinnidine nucleotides could be modified as 2'-deoxy-2'-fluoronucleotides, one or more purine nucleotides could be modified as 2'-deoxypurine nucleotides and, moreover, wherein terminal cap modifications could be present at the 3' or 5' ends; particularly by the introduction of one or more 2'-deoxythynnidine nucleotides, or by the introduction of one or more phosphorothioate groups linking any nudeotides in the sequence but especially at the 3' and 5' end . In addition, a 3'-terminal phosphate or vinylphosphonate group could be introduced. Examples of such modifications would include but not be limited to modifications to the ribose moieties of the nucleotides such as: 2'-deoxy, 2'-deoxyfluoro, 2'-nnethoxy (2'-0-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320;
Jackson et al., (2006) RNA 12, 1197-1205), and 2'-methoxyethyl, wherein it is understood that the stereochennistry of the 2'-substituent could be in the ribo- or arabino- orientation. Another modification could be 2'-trifluoronnethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2'-carbon of the sugar moiety is covalently linked to the 4'-carbon of the sugar moiety by a methylene or nnethoxynnethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2' and C3' to afford "open" chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA
nucleotides could also be replaced by a nnorpholino group to afford PMO
nucleotides. Modifications to the phosphate diester moieties of the nudeotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphorannidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the strand could be modified with 2'-deoxynucleotides such as dT and, further, the dT nudeotides could be modified by phosphorothioate groups in place of diphosphate esters. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference.
Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA
as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150; 883-894.

[0085] In another embodiment, an "RNAi" for use in the compositions, uses, and methods of the invention is a double-stranded RNA and is referred to herein as a "double stranded RNAi agent,"
"double-stranded RNA (dsRNA) molecule," "dsRNA agent," or "dsRNA". The term "dsRNA" refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having "sense" (passenger) and "antisense" (guide) orientations with respect to a target RNA, i.e., a CD320 gene or LRP2 gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi.

[0086] In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonudeotide and/or a modified nucleotide.
In addition, as used in this specification, an "RNAi agent" may include ribonucleotides with chemical modifications (Corey et al., (2018) Nuc Acid Res 46; 1584-1600); an RNAi agent may include substantial modifications at multiple nudeotides or at a single nucleotide. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by "RNAi agent" for the purposes of this specification and claims.
Examples of such modifications would indude but not be limited to modifications to the ribose moieties of the nudeotides such as: 2'-deoxy, 2'-deoxyfluoro, 2'-nnethoxy (2'-0-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205) , and 2'-methoxyethyl, wherein it is understood that the stereochennistry of the 2'-substituent could be in the ribo- or arabino- orientation. Another modification could be 2'-trifluoronnethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2'-carbon of the sugar moiety is covalently linked to the 4'-carbon of the sugar moiety by a methylene or nnethoxynnethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2' and C3' to afford "open" chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA
nucleotides could also be replaced by a nnorpholino group to afford PMO
nucleotides. Modifications to the phosphate diester moieties of the nucleotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphorannidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the sense and antisense strands could be modified with 2'-deoxynucleotides such as dT and, further, the dT nucleotides could be modified by phosphorothioate groups in place of diphosphate esters (FIG.
19).

[0087] Chemical modifications to the ribonucleotides could be made at any individual or combination of nucleotides in the antisense and sense strands. In some cases, all the nucleotides in either the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Allerson et al., (2005) J Med Chem 48, 901-904). In other cases, only some of the nucleotides in the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Chiu et al., (2003) RNA 9, 1034-1048). In yet other cases, the modifications could follow a pattern of alternating 2'-nnethoxy and 2'-fluoro modifications to either or both strands of the siRNA and sometimes the complementary nucleotides of the antisense and sense strands could contain chemical modifications which are not identical, for example, where one member of a complementary nucleotide pair has a 2'-nnethoxy modification and the other member has a 2'-fluoro modification (Choung et al. (2006) Biochenn Biophys Res Connnnun 342, 919-927;
Hassler et al., (2018) Nucleic Acid Res 46, 2185-2196).

[0088] The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3'-end of one strand and the 5'-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a "hairpin loop." Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3'-end of one strand and the 6-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a "linker." The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi agent may comprise one or more nucleotide overhangs.

[0089] In one embodiment, an RNAi agent of the invention is a dsRNA of 20-30 nucleotides that interacts with a target RNA sequence, e.g., a CD320 target mRNA sequence or a LRP2 target mRNA sequence, to direct the deavage of the target RNA.

[0090] The term "antisense strand" refers to the strand of a double stranded RNAi agent which includes a region that is substantially complementary to a target sequence (e.g., a human CD320 mRNA or a LRP2 mRNA). As used herein, the term "region complementary to part of an mRNA encoding CD320 or LRP2" refers to a region on the antisense strand that is substantially complementary to part of a mRNA sequence that codes for either CD320 or LRP2.
Where the region of connplennentarity is not fully complementary to the target sequence, the mismatches are most tolerated in the terminal regions and, if present, are generally in a terminal region or regions, e.g., within 6, 5, 4, 3, or 2 nucleotides of the 6 and/or 3 terminus. For example, substantially complementary can in certain embodiments mean that in a hybridized pair of nucleobase sequences, at least 85% but not all of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynudeotide.

[0091] The term "sense strand," as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.

[0092] As used herein, the term "cleavage region" refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13.

[0093] As used herein, and unless otherwise indicated, the term "complementary," when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nudeotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may indude: 400 mM
NaCI, 40 mM PIPES pH 6.4, 1 mM EDTA, 50 C. or 70 C for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. For example, a complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi. The skilled person will be able to determine the set of conditions most appropriate for a test of connplennentarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

[0094] Sequences can be "fully complementary" with respect to each when there is base-pairing of the nucleotides of the first nucleotide sequence with the nucleotides of the second nucleotide sequence over the entire length of the first and second nucleotide sequences. However, where a first sequence is referred to as "substantially complementary" with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application.
However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as "fully complementary" for the purposes described herein.

[0095] "Complementary" sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled.
Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing.

[0096] The terms "complementary," "fully complementary" and "substantially complementary" herein may be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of a dsRNA
and a target sequence, as will be understood from the context of their use.

[0097] As used herein, a polynucleotide that is "substantially complementary to at least part of" a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding CD320 or an mRNA encoding LRP2) including a 5 UTR, an open reading frame (ORF), or a 3' UTR. For example, a polynucleotide is complementary to at least a part of a CD320 mRNA or LRP2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding CD320 or LRP2.

[0098] The term "inhibiting," as used herein, is used interchangeably with "reducing,"
"silencing," "downregulating," "suppressing" and other similar terms, and includes any level of inhibition.

[0099] The phrase "inhibiting expression of a CD320,"
"inhibiting expression of a LRP2" as used herein, includes inhibition of expression of any CD320 or LRP2 gene (such as the identified gene from, e.g., a mouse, a rat, a monkey, or a human) as well as variants, (e.g., naturally occurring variants), or mutants of the identified gene. Thus, the CD320 or LRP2 gene may be a wild-type CD320 or LRP2 gene, a mutant CD320 or LRP2 gene, or a transgenic CD320 or LRP2 gene in the context of a genetically manipulated cell, group of cells, or organism.

[00100] "Inhibiting expression of a CD320 gene" or "Inhibiting expression of a LRP2 gene"
includes any level of inhibition of a CD320 gene or a LRP2 gene, e.g., at least partial suppression of the expression of a CD320 or LRP2 gene, such as an inhibition of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%. at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. In a preferred embodiment the inhibition is assessed by expressing the level of CD320 or LRP2 protein in treated cells as a percentage of the level of mRNA in control cells, using the following formula:
Normalized protein level for treated cells/Normalized protein level for control cells. The control cells are the negative control siRNA. Normalized means the protein level is normalized to the level of a housekeeping protein.

[00101] The expression of a CD320 or LRP2 gene may be assessed based on the level of any variable associated with CD320 or LRP2 gene expression, e.g., CD320 or LRP2 mRNA level, CD320 or LRP2 protein level. Inhibition may be assessed by a decrease in an absolute or relative level of one or more of these variables compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control).

[00102] Contacting a cell with a RNAi agent, either ds or ss as used herein, includes contacting a cell by any possible means whether in vivo or in vitro.
Contacting a cell with a RNAi agent includes contacting a cell in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell.

[00103] A "patient" or "subject," as used herein, is intended to include either a human or non-human animal, preferably a mammal, e.g., a monkey. Most preferably, the subject or patient is a human.

[00104] A "CD320-associated disease," as used herein, is intended to include any disease associated with a perturbation of the CD320 gene, or protein, polynnorphisnns, single nucleotide polymorphisms (SNPs) as well as epigenetic modifications of the CD320 gene.
Such a disease may be caused, for example, by excess production of the CD320 protein, by CD320 gene mutations, by abnormal cleavage of the CD320 protein, by abnormal folding of the CD320 protein, by abnormal interactions between CD320 itself or with other proteins or other endogenous or exogenous substances. For example, cancer may be a CD320-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

[00105] A "LRP2-associated disease," as used herein, is intended to include any disease associated with a perturbation of the LRP2 gene, protein, polynnorphisnns, SNPs as well as epigenetic modifications of the CD320 gene. Such a disease may be caused, for example, by excess production of the LRP2 protein, by LRP2 gene mutations, by abnormal cleavage of the LRP2 protein, by abnormal folding of the LRP2 protein, by abnormal interactions between LRP2 molecules and other proteins or other endogenous or exogenous substances. For example, cancer may be a LRP2-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

[00106] "Therapeutically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a cell or a patient for treating a CD320 associated disease or a LRP2 associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or by preferentially causing the death of a disease cell as compared to a non-disease cell). The "therapeutically effective amount" may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by CD320 or LRP2 expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[00107] "Prophylactically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject who does not yet experience or display symptoms of a CD320 associated disease or a LRP2 associated disease, but who may be predisposed to the disease, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[00108] A "therapeutically-effective amount" or "prophylactically effective amount" also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. RNAi agents employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.
Pharmaceutical Compositions

[00109] The methods described herein include administration of a LRP2 inhibiting composition and/or a CD320 inhibiting composition, e.g., a first siRNA
targeting a CD320 gene and/or a second siRNA targeting a LRP2 gene. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

[00110] The methods described herein also include administration of one or multiple LRP2 inhibiting compositions and/or one or multiple CD320 inhibiting compositions, e.g., one or more siRNAs targeting a CD320 gene and/or one or more siRNAs targeting an LRP2 gene. It is understood that such compositions could be chemically modified in a variety of ways and that such modifications need not be identical in compositional mixtures. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

[00111] The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical, pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdernnal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intraparenchymal, intrathecal or intraventricular, administration.

[00112] The compositions can be delivered in a manner to target a particular tissue, such as the lung cells or breast cells or brain cells or bladder cells or uterine cells or cervix cells or prostate cells. Pharmaceutical compositions can be delivered by injection directly into the brain. The injection can be by stereotactic injection into a particular region of the brain (e.g., the substantia nigra, cortex, hippocannpus, striatum, or globus pallidus), or the dsRNA can be delivered into multiple regions of the central nervous system (e.g., into multiple regions of the brain, and/or into the spinal cord). The dsRNA can also be delivered into diffuse regions of the brain (e.g., diffuse delivery to the cortex of the brain). In general siRNAs are administered 1) by intratunnoral injection, 2) by systemic injection, 3) by slow release from an implanted polymer. Other tissue specificity could be achieved by antibody or small molecule conjugation, or by a tissue-specific delivery device (e.g., a catheter can be used to deliver to the bladder).

[00113] In one embodiment, an RNAi targeting either LRP2 or the CD320 can be delivered by way of a cannula or other delivery device having one end implanted in a tissue. The cannula can be connected to a reservoir of the RNAi composition. The flow or delivery can be mediated by a pump, e.g., an osmotic pump or minipump. In one embodiment, a pump and reservoir are implanted in an area distant from the tissue, e.g., in the abdomen, and delivery is affected by a conduit leading from the pump or reservoir to the site of release.

[00114] Accordingly, in some embodiments, the pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions described herein are formulated for administration to a subject.

[00115] As used herein, a pharmaceutical composition or medicament includes a pharmacologically effective amount of at least one of the described RNAi agents and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical Ingredient (API, therapeutic product, e.g., CD320 RNAi agent or LRP2 RNAi agent) that are intentionally included in the drug delivery system.
Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage.
Excipients can act to a) aid in processing of the drug delivery system during manufacture, b) protect, support, or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

[00116] Excipients include, but are not limited to:
absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, hunnectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

[00117] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers indude physiological saline, bacteriostatic water, Cremophor®
ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The composition, understood to include formulations and drug delivery systems, should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum nnonostearate and gelatin.

[00118] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[00119] Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in nnicrocrystalline form, for example, in the form of an aqueous nnicrocrystalline suspension. Liposonnal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

[00120] The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and nnicroencapsulated delivery systems. Biodegradable, bioconnpatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
Liposonnal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S.
Pat. No. 4,522,811.

[00121] Dosage and Timing The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the LRP2 inhibiting composition and or the CD320 -inhibiting compositions encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein.

[00122] In general, a suitable dose of a pharmaceutical composition of the LRP2 inhibiting composition and/or the CD320 -inhibiting composition will be in the range of 0.01 to 300.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day.

[00123] For example, the LRP2 inhibiting composition and/or the CD320 -inhibiting composition can be an siRNA composition of one or more siRNAs, and can be administered at, 0.01 mg/kg, 0.05 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.628 mg/kg, 2 mg/kg, 3 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 400 mg/kg per single dose. In another embodiment, the dosage is between 0.15 mg/kg and 0.3 mg/kg.
For example, the LRP2 and/or the CD320 -inhibiting composition can be administered at a dose of 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, or 0.3 mg/kg. In an embodiment, the LRP2 and/or the CD320 -inhibiting composition is administered at a dose of 0.3 mg/kg.

[00124] The pharmaceutical composition may be administered once daily, or once or twice every 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. The dosage unit can be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the LRP2 inhibiting composition and/or the CD320 -inhibiting composition over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention.

[00125] In an embodiment, the LRP2 -inhibiting composition and/or the CD320 -inhibiting composition is dependent upon the tumor cell line, and the dosage is 0.3 mg/kg, and wherein the dose is administered once every 21 days. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered once every 21 days via a 70 minute infusion of 1 mUmin for 15 minutes followed by 3 nnUnnin for 55 minutes. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered at two doses every 21-28 days via a 60 minute infusion of 3.3 mUmin, or via a 70 minute infusion of 1.1 mUmin for 15 minutes followed by 3.3 mUmin for 55 minutes

[00126] A dosage of a LRP2 -inhibiting composition and/or the CD320 -inhibiting composition can be adjusted for treatment

[00127] A LRP2 -inhibiting composition and/or the CD320 -inhibiting composition can be administered in combination with other known agents effective in treatment of pathological processes mediated by target gene expression.

[00128] In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

[00129] In embodiments of the pharmaceutical compositions described herein, the RNAi (e.g., dsRNA) is administered with a buffer solution. In embodiments, the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In embodiments, the buffer solution is phosphate buffered saline (PBS).

[00130] In embodiments of the pharmaceutical compositions described herein, the composition is administered intravenously.

[00131] In embodiments of the pharmaceutical compositions described herein, the composition is administered subcutaneously.

[00132] In certain embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a lipid formulation. In embodiments, the composition is administered intravenously.

[00133] In some embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a cationic polyannine formulation or nanoparticle (e.g., JetPEI). In some embodiments, the composition is administered intravenously.

[00134] In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

[00135] In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 or CD320, is administered with a non-RNAi therapeutic agent, such as an agent known to treat a cancer such as lung cancer. In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA
targeting LRP2 and/or CD320, is administered along with a non-RNAi therapeutic regimen, such as radiation, chemotherapy, imnnunotherapy, photodynannic therapy or a combination thereof.

[00136] In an aspect provided herein is a method of inhibiting LRP2 and/or CD320 expression in a cell, the method comprising: (a) introducing into the cell an RNAi agent (e.g., a dsRNA) described herein and (b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the nnRNA
transcript of an LRP2 gene and/or CD320 gene, thereby inhibiting expression of the LRP2 gene and/or CD320 gene in the cell.

[00137] In an aspect provided herein is a method for reducing or inhibiting the expression of LRP2 gene and/or CD320 genes in a cell. The method includes: (a) introducing into the cell one or more complimentary double-stranded ribonudeic acid (dsRNA) molecules, in which one sequence is designated the sense strand and the other sequence the anti-sense strand, and wherein the anti-sense strand has significant connplennentarity to a portion of mRNA encoding for LRP2 or CD320. The complimentary region is 15-30 nucleotides in length, and generally 19-24 nucleotides in length, and the dsRNA, upon entering a cell expressing LRP2 and/or CD320, inhibits the expression of the LRP2 protein and/or CD320 protein by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more;
(b) single or repeated treatment of the cell with dsRNAs, as described in part (a), so as to maintain the inhibition of LRP2 and/or CD320 protein expression over a desired period of time by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more.

[00138] In embodiments of the foregoing methods of inhibiting LRP2 and/or CD320 expression in a cell, the cell is treated ex vivo, in vitro, or in vivo. In embodiments, the cell is a melanoma, glioblastonna, lung carcinoma, triple negative breast carcinoma, renal carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian carcinoma and prostate carcinoma.

[00139] In some embodiments, the cell is present in a subject in need of treatment, prevention and/or management of a CD320-associated disease or a LRP2-associated disease.

[00140] In embodiments, the expression of LRP2 and/or CD320 is inhibited by at least 30%.

[00141] In embodiments, the RNAi (e.g., dsRNA) has an IC50 in the range of 0.01-50 nM.

[00142] In embodiments, the RNAi (e.g., dsRNA) has an IC50 in the range of 0.01-1 nM.

[00143] In certain embodiments, the cell is a mammalian cell (e.g., a human, non-human primate, or rodent cell).

[00144] In one embodiment, the cell is treated ex vivo, in vitro, or in vivo (e.g., the cell is present in a subject (e.g., a patient in need of treatment, prevention and/or management of a disorder related to LRP2 and/or CD320 expression).

[00145] In one embodiment, the subject is a mammal (e.g., a human) at risk, or diagnosed with a proliferation disorder.

[00146] In embodiments, the RNAi (e.g., dsRNA) is formulated as an lipid nanoparticle (LNP) polyplex (polyamine) formulation.

[00147] In embodiments, RNAi (e.g., dsRNA) is administered at a dose of 0.05001-500.01 mg/kg.

[00148] In embodiments, the RNAi (e.g., dsRNA) is administered at a concentration of 0.01 mg/kg-50.1 ring/kg bodyweight of the subject.

[00149] In embodiments, the RNAi (e.g., dsRNA) is formulated as an LNP formulation and is administered at a dose of 0.050.1-50.5 ring/kg.

[00150] In embodiments, the RNAi (e.g., dsRNA) has an IC50 in the range of 0.01-10 nM.

[00151] In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered according to a dosing regimen. In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered as a single dose or at multiple doses, e.g., according to a dosing regimen.

[00152] The term "sample," as used herein, includes a collection of fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from a tumor. In preferred embodiments, a "sample derived from a subject" refers to blood or plasma drawn from the subject. In further embodiments, a "sample derived from a subject" refers to tissue biopsy derived from the subject.

[00153] In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group consisting of the sense sequences of Table 1 and a second sequence that is selected from the group consisting of the corresponding antisense sequences of Table 1. It is understood that the suffix A (e.g., OSC17A) represents the antisense strand whereas the suffix S (e.g., OSC175) represents the sense strand. In those instances when we refer to an siRNA with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC175).

[00154] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated in a stable nucleic acid lipid particle (SNALP).

[00155] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated in a stable nucleic acid lipid particle (SNALP).

[00156] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyannine.

[00157] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyannine.

[00158] Referring now to Table 1 ¨ DNA sequences are illustrated, which are subsequently transcribed into shRNA, which hence targets the CD320 or LRP2 mRNA for destruction in the cell.
shRNA sequences used in lentiviral vectors illustrates the sequences that were used to target the CD320 sequence coding for the CD320 protein and the LRP2 sequence coding for the LRP2 protein.

The Each vector that carried a shRNA coding sequence also contained a unique drug resistance gene which would allow for selecting those cells that had taken up the shRNA as those cells that had not taken up the shRNA having the unique drug resistance gene would not survive.
On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. The cells that were infected with the irrelevant control shRNA kept on growing as expected (since the shRNA was essentially a non-functional shRNA) ¨ data not shown. The results for the cell lines that took up the CD320+LRP2 shRNAs are shown in Table 1.
Table 1 Name Target Sense Sequence Anti-Sense Sequence Locatio n in DNA
shScramble non-targeting control CCTAAGGTTAAGTCGCCCTC
CGAGGGCGACTTAACCTTAG N/A
G (SEQ ID NO. 941) G (SEQ ID NO. 942) shCD320-#27 C0320 CCCTCAGAGACCTGAGCTCT

(NM_016579.3) T G (SEQ ID NO. 944) (SEQ ID NO. 943) shLRP2-#89 LRP2 (NM_004525.2) CCTGTAATAAACACTACTCTT

G (SEQ ID NO. 946) (SEQ ID NO. 945) The preliminary studies show that cancer cells are selectively killed by CD320 and LRP2 knockdown, while normal cells remain unaffected (Table 2).

[00159] Table 2 shows the effect of simultaneous knockdown of CD320 and LRP2 on cell viability.
Table 2 Outcome of CD320/LRP2 knockdown Cell arrest/death Alive Cancer (Lung) HCC15 -\I
H157 -\I
H358 -\I
H1999 -\I
Non-cancer Normal fibroblast -\I

LDLR mutant fibroblast

[00160] Additional cancer cell lines were also treated with the compounds described herein to determine whether cancer cell lines were more susceptible to growth inhibition and toxicity as compared to non-cancer cells of the same origin. Cell lines from skin, prostate, and brain cancers were screened similarly to the experimental outline in FIG. 1. Table 3 summarizes the effects of simultaneous knockdown of CD320 and LRP2 in cancer and normal cells.
Table 3 Cell shSCR shCD320 shLRP2 shCD320+shLRP2 Comments Normal cells 6M05659 +++ +++ +++ +++ no effect of knockdown 6M00701 +++ +++ +++ cells grow very slow;
hard to determine if any affect of knockdown SAEC pending Lung cells HCC15 +++ cells strongly affected by knockdown H157 +++ ++ senescent phenotype H358 +++ ++ ++ morphology changes; cells rounded H1993 +++ ++ cells rounded; morphology change Melanoma Cells morphology change; cells strongly affected b double MDA-MB-4353 +++ knockdown Prostate cells LncAP +++ ++ cells rounded; morphology change PC3 +++ +++ ++ +++ cells minimally to not affected by knockdown DU-145 +++ ++ cells modestly affected by knockdown Glioblastoma A172 +++ 0 cells strongly affected by knockdown U251MG +++ ++ 0 cells strongly affected by knockdown U343 +++ +++ ++ +++ cells modestly affected by LRP2 knockdown T98G +++ +++ ++ ++ cells slightly affected by knockdown F++ cells unaffected compared to shSCR (control) F+ cells modestly affected compared to shSCR (control) + cells significantly affected compared to shSCR (control) 0 vast majority of cells killed compared to shSCR (control)

[00161] The screening results showed that lung, prostate, skin, and brain cancer cell lines were growth-inhibited or killed by the simultaneous knockdown ("double knockdown") of CD320 and LRP2, while non-cancerous cells were unaffected.

[00162] Referring now to FIG. 2, representative pictures of the cells were taken to record their phenotypes after the double knockdown of CD320 and LRP2 and to illustrate the sensitivity of cancer cell lines to knockdown of the expression of CD320 and LRP2 proteins.

[00163] Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1. The cells were grown as described in FIG. 1. On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid line ovals indicate healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cells of cancer cell lines infected with shRNAs to CD320 and LRP2.

[00164] These results support use of the compounds as therapeutics based upon decreasing expression of CD320 and LRP2 protein preferentially resulting in detrimental effects in cancer cells as compared to non-cancer cells. The original experiments were conducted using shRNAs delivered by lentiviral vectors. Short inhibitory RNAs (siRNAs), having a sequence complimentary to a portion of the CD320 protein and/or the LRP2 protein were designed. The siRNAs can be chemically modified to increase their stability and potency and reduce their innnnunogenicity, and multiple platforms exist for their delivery in clinical applications.

[00165] siRNA sequences that efficiently knock down the protein levels of LRP2 and/or CD320 were designed and identified. Table 4 is a list of siRNA sequences complementary to nnRNA
for CD320 or LRP2 that were tested for their ability to knock down CD320 or LRP2 protein, respectively (see FIG. 3, FIG. 4, FIG. 5, FIG. 12, and FIG. 15).
Table 4 ID Passenger Sequence Target Size Nucleotide Location start site OSS1 CCUAAGGUUAAGUCGCCCUCG (SRI none 21 N/A N/A
ID NO. 947) OSS2 UGGUUUACAUGUUGUGUGA (SEQ ID none 19 N/A N/A
NO. 948) CAAA (SKI ID NO. 949) NM_004525.2 CAUUGCAAA (SRI ID NO. 950) NM_004525.2 0SL47 CCUGUAAUAAACACUACUCUU (SEQ LRP2 21 2800 CDS
ID NO. 951) NM_004525.2 0SL104 CCUUCUAUGAACCUGGCCUUA (SKI LRP2 21 5677 CDS
ID NO. 952) NM_004525.2 0SL90 GUGAUUUGAUUAUACGGCA (SEQ ID LRP2 19 5126 CDS
NO. 953) NM_004525.2 OSL119 CCUCAAAUGGCUGUAGCAA (SEQ ID LRP2 19 6266 CDS
NO. 954) NM_004525.2 NM_016579.3 (SKI ID NO. 955) 0SC47 CCCUCAGAGACCUGAGCUCUU (SRI CD320 21 1006 3'-UTR
ID NO. 956) NM_016579.3

[00166] The list of all potential siRNA sequences is quite large. We have identified 340 potential siRNA sequences to LRP2 and 59 potential siRNA sequences to CD320.
(See Table 5 and Table 6 for the complete list and Table 5A and Table 6A identify the target position and sequence that is complementary for each antisense sequence identified). In addition, chemical modifications can be made to these siRNA sequences to improve their stability and reduce their off-target effects.
siRNA molecules are vulnerable to metabolic degradation, for example by RNase or DNase enzymes.
Chemical modification of siRNA molecules by incorporation of one or more unnatural, that is, manmade, nucleotides within the sequence can render siRNAs resistant to such metabolic degradation and increase their biological half-life in the cell or in plasma.
Moreover, the indusion of manmade nucleotides at strategic locations within the siRNA sequence can decrease the immunogenicity of the siRNA and improve the selectivity for the guide strand over the passenger strand. Modified siRNA molecules may incorporate manmade nucleotides of a single type or may include multiple manmade nucleotides of different types. Manmade nucleotides may include, but are not limited to, those which contain chemical modifications to the ribose moiety or to the phosphate moieties (FIG. 19 and Table 7). Examples of manmade nucleotides indude, but are not limited to, the structures shown in the Table 7. Moreover, modification of multiple structural elements may be combined. In addition, modification may be made to the nucleobase B, which, in addition to the natural RNA nucleobases (G, C, A, U), may include unnatural bases, such as those containing a sulfur atom (e.g., thiouracil).
Table 7. Nucleotide modifications corresponding to FIG. 19A
Designationa Y XZ R R' B
(nucleobase) [2fN] 0 0 0 F H G, C, A, U, other 2'-FANA 0 0 0 H F G, C, A, U, other [mN] 0 0 0 OMe H G, C, A, U, other 2'-MOE 0 0 0 CH2CH20Me H G, C, A, U, other 2'-EA 0 0 0 CH2CH2NH2 H G, C, A, U, other 2'-DMEA 0 0 0 CH2CH2NMe2 H G, C, A, U, other 2'-DMAP 0 0 0 CH2CH2CH2NMe2 H G, C, A, U, other * as in N1*N2 0 S 0 OH H G, C, A, U, other ** as in N1**N2 S S 0 OH H G, C, A, U, other 2'-deoxy 0 0 0 H H G, C, A, U, other 4'-S 0 0 S H H G, C, A, U, other F-SRNA 0 0 S F H G, C, A, U, other Me-SRNA 0 0 S OMe H G, C, A, U, other 4'-S-FANA 0 0 S H F G, C, A, U, other a N designates an arbitrary ribonucleotide or deoxyribonucleotide or analogs thereof.
In some embodiments, chemical modification is made to the phosphodiester group which covalently connects two nucleotides, such that, for example, one or two oxygen atoms in that group are substituted with sulfur atoms, as indicated by a single or double asterisk between two nucleotides to represent the replacement of one or two oxygen atoms with sulfur in the phosphodiester (Table 7 and FIG. 19A). In some embodiments, the siRNA sequences may include other manmade nucleotides wherein further structural modifications have been made to the ribose moiety, such as the addition of bridging atoms that covalently link carbons 2' and 5' of the ribose moiety (FIG. 19B-C) or positions 1' and 2' of the ribose moiety (FIG. 19D), or alternatively, changes to the size of the sugar ring in a given nucleotide, for example, deletion of the bond between carbons 2' and 3' of the ribose moiety (FIG.
19E), or increasing the size of the sugar ring from five to six atoms (FIG.
19F-G).

OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') OSC4A AUCCAACCGCCGCUCAUGCUG [dT][dT] (SEQ 05C45 CAGCAUGAGCGGCGGUUGGAU [dT] [dT]
ID NO 4) (SEQ ID NO: 97) OSC8A ACUGGAACUUGGUGGG UGG GC [dT] [dT] (SEQ 05C85 GCCCACCCACCAAGUUCCAGU[dT][dT]
ID NO 8) (SEQ ID NO: 101) OSC12A UCCUCAUCGCUGCCAUCGCUG [dT] [dT] (SEQ 05C125 CAGCGAUGGCAGCGAUGAGGA[dT]
[dT]
ID NO 12) (SEQ ID NO: 105) OSC16A AGUUUCUUGUCAGUUCCCCCA[dT] [dT] (SEQ 05C165 UGGGGGAACUGACAAGAAACU[dT]
[dT]
ID NO 16) (SEQ ID NO: 109) OSC31A UUCCAGACUGGUCUCCGGCAG [dT] [dT] (SEQ 05C315 CUGCCGGAGACCAGUCUGGAA[dT][dT]
ID NO 48) (SEQ ID NO: 141) 05C35A ACAAAAGGAGGAGGGUGGCGG[dT] [dT] (SEQ 05C355 CCGCCACCCUCCUCCUUUUGU [dT]
[dT]
ID NO 52) (SEQ ID NO: 145) OSC40A UCUGUUCUGACAGCAGCAGGG[dT][dT] (SEQ 05C405 GGCUGCUGCUGUCAGAACAGA[dT][dT]
ID NO 57) (SEQ ID NO: 150) 05C46A UCUCUGAGGGCUGGUGUGCCC[dT][dT] (SEQ 05C465 GGGCACACCAGCCCUCAGAGA[dT][dT]
ID NO 63) (SEQ ID NO: 156) 05C57A AGUGUCUUAAGCACAGGGCCG [dT] [dT] (SEQ 05C575 CGGCCCUGUGCUUAAGACACU[dT][dT]
ID NO: 91) (SEQ ID NO: 184) 05C59A UUUUUUUGAGGAUGUGAAGCA[dT] [dT] 05C595 UGCUUCACAUCCUCAAAAAAA[dT][dT]
(SEQ ID NO: 93) (SEQ ID NO: 186) OSC10A ACGCAUAAGCCACUGGUGCGG [dT] [dT] (SEQ OSC10S CCGCACCAGUGGCUUAUGCG
U[dT][dT]
ID NO 10) (SEQ ID NO: 103) OSC11A UCCAAGUCCCUGUCGCAGCGC[dT][dT] (SEQ OSC11S GCGCUGCGACAGGGACUUGGA[dT][dT]
ID NO 11) (SEQ ID NO: 104) OSC13A UCACUGACGCCGGUGCAGGGG [dT] [dT] (SEQ 05C135 CCCCUGCACCGGCGUCAGUGA[dT]
[dT]
ID NO 13) (SEQ ID NO: 106) OSC14A UUGUCAGUUCCCCCAGAGCAG [dT] [dT] (SEQ 05C145 CUGCUCUGGGGGAACUGACAA[dT][dT]
ID NO 14) (SEQ ID NO: 107) OSC15A UUCUUGUCAGUUCCCCCAGAG [dT] [dT] (SEQ 05C155 CUCUGGGGGAACUGACAAGAA[dT]
[dT]
ID NO 15) (SEQ ID NO: 108) OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT] [dT 05C175 GAACUGACAAGAAACUGCGCAACUG
1 ] (SEQ ID NO 17) -1 [dT][dT] (SEQ ID NO:
110) OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT]*[d 05C175 2 T] (SEQ ID NO 18) -2 GAACUGACAAGAAACUGCGCAACUG[dT]*
[dT] (SEQ ID NO: 111) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] 05C175 [mG][mA][mA][mC][mU][mG][mA][mC][
3 [mA][mG][mU][mU][mU][mC][mU][mU][mG -3 ..
mA][mA][mG][mA][mA][mA][mC][mU][m ][mU][mC][mA][mG][mU][mU][mC][dT]*[dT]
G][mC][mG][mC][mA][mA][mC][mU][mG]
] (SEQ ID NO 19) [dT]*[dT] (SEQ ID
NO: 112) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] 05C175 4 [mA][mG][mU][mU][mU][mC][mU][mU][mG -4 [mG][mA][mA][mC][mU][mG][mA][mC][
][mU][mC][mA][mG][mU][mU][mC][dT]*[dT]
mA][mA][mG][mA][mA][mA][mC][mU][m ] (SEQ ID NO 20) G][mC][mG][mC][mA][mA][mC][mU][mG]
(SEQ ID NO: 113) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] 05C175 [mG][mA][mA][mC][mU][mG][mA][mC][
[mA][mG][mU][mU][mU][mC][mU][mU][mG -5 mA][mA][mG][mA][mA][mA][mC][mU][m ][mU][mC][mA][mG][mU][mU][mC] ] (SEQ ID
G][mC][mG][mC][mA][mA][mC][mU][mG]
NO 21) [dT]*[dT] (SEQ ID
NO: 114) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] 05C175 [mG][mA][mA][mC][mU][mG][mA][mC][
6 [mA][mG][mU][mU][mU][mC][mU][mU][mG -6 mA][mA][mG][mA][mA][mA][mC][mU][m ][mU][mC][mA][mG][mU][mU][mC] ] (SEQ ID
G][mC][mG][mC][mA][mA][mC][mU][mG]
NO 22) (SEQ ID NO: 115) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] 05C175 7 [mA][mG][mU][mU][mU][mC][mU][mU][mG -7 GAACUGACAAGAAACUGCGCAACUG[dT]*
][mU][mC][mA][mG][mU][mU][mC][dT]*[dT] [dT] (SEQ ID NO:
116) ] (SEQ ID NO 23) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 [2fG][mA][2fA][mC][2fU][mG][2fA][mC][2 8 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -8 fA][mA][2fG][mA][2fA][mA][2fC][mU][2f ][mU][2fC][mA][2fG][mU][2fU][mC][dT]*[dT]
G][mC][2fG][mC][2fA][mA][2fC][mU][2fG
(SEQ ID NO 24) ][dT]*[dT] (SEQ ID
NO: 117) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 [2fG][mA][2fA][mC][2fU][mG][2fA][mC][2 9 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -9 fA][mA][2fG][mA][2fA][mA][2fC][mU][2f ][mU][2fC][mA][2fG][mU][2fU][mC] (SEQ ID
G][mC][2fG][mC][2fA][mA][2fC][mU][2fG
NO 25) ][dT]*[dT] (SEQ ID
NO: 118) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 [2fG][mA][2fA][mC][2fU][mG][2fA][mC][2 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -10 fA][mA][2fG][mA][2fA][mA][2fC][mU][2f ][mU][2fC][mA][2fG][mU][2fU][mC][dT]*[dT]
G][mC][2fG][mC][2fA][mA][2fC][mU][2fG
(SEQ ID NO 26) ] (SEQ ID NO: 119) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 11 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -11 [2fG][mA][2fA][mC][2fU][mG][2fA][mC][2 ][mU][2fC][mA][2fG][mU][2fU][mC] (SEQ ID
fA][mA][2fG][mA][2fA][mA][2fC][mU][2f NO 27) G][mC][2fG][mC][2fA][mA][2fC][mU][2fG
] (SEQ ID NO: 120) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG][2fC] 05C175 12 [mA][2fG][mU][2fU][mU][2fC][mU][2fU][mG -12 [mG][2fA][mA][2fC][mU][2fG][mA][2fC][

OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') ][2fU][mC][2fA][mG][2fU][mU][2fC][dT]*[dT]
mA][2fA][mG][2fA][mA][2fA][mC][2fU][m (SEQ ID NO 28) G][2fC][mG][2fC][mA][2fA][mC][2fU][mG
][dT]*[dT] (SEQ ID NO: 121) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG][2fC] 05C175 [mG][2fA][mA][2fC][mU][2fG][mA][2fC][
13 [mA][2fG][mU][2fU][mU][2fC][mU][2fU][mG -13 mA][2fA][mG][2fA][mA][2fA][mC][
][2fU][mC][2fA][mG][2fU][mU][2fC] (SEQ ID
2fU][mG][2fC][mG][2fC][mA][2fA][mC][2f NO 29) U][mG] (SEQ ID NO:
122) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC][2fG][2fC] 05C175 [2fU][mG][2fA][mC][2fA][mA][2fG][mA][2 14 [2fA][2fG][2fU][2fU][2fU][2fC][2fU][2fU][2fG -14 fA][mA][2fC][mU][2fG][mC][2fG][mC][2fA
][2fU][2fC][2fA][2fG][2fU][2fU][2fC][dT]*[dT]
][mA][2fC][mU][2fG][dT]*[dT] (SEQ ID
(SEQ ID NO 30) NO: 123) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC][2fG][2fC] 05C175 15 [2fA][2fG][2fU][2fU][2fU][2fC][2fU][2fU][2fG -15 [2fG][mA][2fA][mA][2fC][mU][2fG][mC][2 ][2fU][2fC][2fA][2fG][2fU][2fU][2fC][dT]*[dT]
fG][mC][2fA][mA][2fC][mU][2fG][dT]*[dT
(SEQ ID NO 31) ] (SEQ ID NO: 124) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 16 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -16 [2fG][mA][2fA][mA][2fC][mU][2fG][mC][2 ][mU][2fC][mA][2fG][mU][2fU][mC][dT]*[dT]
fG][mC][2fA][mA][2fC][mU][2fG][dT]*[dT
(SEQ ID NO 32) ] (SEQ ID NO: 125) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 [2fG][mA][2fA][mA][2fC][mU][2fG][mC][2 17 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG -17 fG][mC][2fA][mA][2fC][mU][2fG] (SEQ ID
][mU][2fC][mA][2fG][mU] (SEQ ID NO 33) NO: 126) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] 05C175 [2fG][mA][2fA][mA][2fC][mU][2fG][mC][2 18 [2fA][mG][2fU][mU][2fU][mC][2fU][2fU][2fG -18 fG][mC][2fA][mA][2fC][mU][2fG] (SEQ ID
][2fU][2fC][2fA][2fG][2fU] (SEQ ID NO 34) NO: 127) OSC18A AUGCAGUCAUCGCUCAGCGUG[dT][dT] (SEQ 05C185 CACGCUGAGCGAUGACUGCAU[dT][dT]
ID NO 35) (SEQ ID NO: 128) OSC19A AAUGCAGUCAUCGCUCAGCGU[dT][dT] (SEQ 05C195 ACGCUGAGCGAUGACUGCAUU[dT][dT]
ID NO 36) (SEQ ID NO: 129) OSC20A UGGAAUGCAGUCAUCGCUCAG[dT][dT] (SEQ 05C205 CUGAGCGAUGACUGCAUUCCA[dT][dT]
ID NO 37) (SEQ ID NO: 130) OSC21A AGUGGAAUGCAGUCAUCGCUC[dT][dT] (SEQ 05C215 GAGCGAUGACUGCAUUCCACU[dT][dT]
ID NO 38) (SEQ ID NO: 131) 05C22A ACAGUCUGGGUGGCCGUCGCA[dT][dT] (SEQ 05C225 UGCGACGGCCACCCAGACUGU[dT][dT]
ID NO 39) (SEQ ID NO: 132) 05C23A AUUGGUUCCACAGCCGAGCUC[dT][dT] (SEQ 05C235 GAGCUCGGCUGUGGAACCAAU[dT][dT]
ID NO 40) (SEQ ID NO: 133) 05C24A UCUCAUUGGUUCCACAGCCGA[dT][dT] (SEQ 05C245 UCGGCUGUGGAACCAAUGAGA[dT][dT]
ID NO 41) (SEQ ID NO: 134) OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') 05C25A AUCUCAUUGGUUCCACAGCCG [dT] [dT] (SEQ 05C255 CGGCUGUGGAACCAAUGAGAU[dT]
[dT]
ID NO 42) (SEQ ID NO: 135) 05C26A AGGAUCUCAU UGGU UCCACAG [dT] [dT] (SEQ 05C265 CUGUGGAACCAAUGAGAUCCU
[dT] [dT]
ID NO 43) (SEQ ID NO: 136) 05C27A UGAGAGAGGUGACACUCUCCA[dT] [dT] (SEQ 05C275 UGGAGAG
UGUCACCUCUCUCA[dT][dT]
ID NO 44) (SEQ ID NO: 137) 05C28A UGGUUGUGGCAUUCCUGAGAG [dT] [dT] 05C285 CUCUCAGGAAUGCCACAACCA[dT][dT]
(SEQ ID NO 45) (SEQ ID NO: 138) 05C29A UGGCAU UCCCGACAGAGGGGA[dT][dT] (SEQ 05C295 UCCCCUCUGUCGGGAAUGCCA[dT][dT]
ID NO 46) (SEQ ID NO: 139) OSC30A AGGAUGUGGCAU UCCCGACAG [dT] [dT] (SEQ 05C305 CUGUCGGGAAUGCCACAUCCU[dT][dT]
ID NO 47) (SEQ ID NO: 140) 05C32A AUAACCCCAUAGGCAG UUGGG [dT] [dT] (SEQ 05C325 CCCAACUGCCUAUGGGGUUAU[dT]
[dT]
ID NO 49) (SEQ ID NO: 142) 05C33A UUGCACUGAGCACCGCAGCAG [dT] [dT] (SEQ 05C335 CUGCUGCGGUGCUCAGUGCAA[dT]
[dT]
ID NO 50) (SEQ ID NO: 143) 05C34A AAAAGGAGGAGGGUGGCGGUG [dT] [dT] (SEQ 05C345 CACCGCCACCCUCCUCCU UUU
[dT][dT]
ID NO 51) (SEQ ID NO: 144) 05C36A ACCAGUAACCCCAGUGGGCGG [dT] [dT] (SEQ 05C365 CCGCCCACUGGGG UUACUGG U[dT]
[dT]
ID NO 53) (SEQ ID NO: 146) 05C37A UUCAUGGCCACCAGUAACCCC[dT][dT] (SEQ 05C375 GGGG
UUACUGGUGGCCAUGAA[dT][dT]
ID NO 54) (SEQ ID NO: 147) 05C38A ACUCCUUCAUGGCCACCAGUA[dT] [dT] (SEQ 05C385 UACUGGUGGCCAUGAAGGAGU[dT]
[dT]
ID NO 55) (SEQ ID NO: 148) 05C39A UUCUGACAGCAGCAGGGACUC[dT][dT] (SEQ 05C395 GAGUCCCUGCUGCUG UCAGAA[dT]
[dT]
ID NO 56) (SEQ ID NO: 149) OSC41A UCU UCUGUUCUGACAGCAGCA[dT][dT] (SEQ 05C415 UGCUGCUGUCAGAACAGAAGA[dT]
[dT]
ID NO 58) (SEQ ID NO: 151) 05C42A AGG UCU UCUGU UCUGACAGCA[dT][dT] (SEQ 05C425 UGCUGUCAGAACAGAAGACCU[dT][dT]
ID NO 59) (SEQ ID NO: 152) 05C43A UUGUCCUCAGGGCAGCGAGG U[dT][dT] (SEQ 05C435 ACCUCGCUGCCCUGAGGACAA[dT]
[dT]
ID NO 60) (SEQ ID NO: 153) 05C44A AAGUGCU UG U CCU CAGGGCAG [dT][dT] (SEQ 05C445 CU GCCCU GAGGACAAGCACU U
[dT] [dT]
ID NO 61) (SEQ ID NO: 154) OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') 05C45A UACCCAUCCGCAUCACUGCUC[dT][dT] (SEQ 05C455 GAGCAGUGAUGCGGAUGGGUA[dT][dT]
ID NO 62) (SEQ ID NO: 155) 05C47A- AAGAGCUCAGGUCUCUGAGGG[dT][dT] (SEQ 05C475 CCCUCAGAGACCUGAGCUCUU
[dT][dT]
1 ID NO 64) -1 (SEQ ID NO: 157) 05C47A- AAGAGCUCAGGUCUCUGAGGG [dT]*[dT] 05C475 CCCUCAGAGACCUGAGCUCUU[dT]*[dT]
2 (SEQ ID NO 65) -2 (SEQ ID NO: 158) 05C47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] 05C475 3 [mG][mG][mU][mC][mU][mC][mU][mG][mA] -3 [mC][mC][mC][mU][mC][mA][mG][mA][
[mG][mG][mG][dT]*[dT] (SEQ ID NO 66) mG][mA][mC][mC][mU][mG][mA][mG][m C][mU][mC][mU][mU][dT]*[dT] (SEQ ID
NO: 159) 05C47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] 05C475 [mC][mC][mC][mU][mC][mA][mG][mA][
4 [mG][mG][mU][mC][mU][mC][mU][mG][mA] -4 mG][mA][mC][mC][mU][mG][mA][mG][m [mG][mG][mG][dT]*[dT] (SEQ ID NO 67) C][mU][mC][mU][mU]
(SEQ ID NO: 160) 05C47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] 05C475 [mC][mC][mC][mU][mC][mA][mG][mA][
[mG][mG][mU][mC][mU][mC][mU][mG][mA] -5 mG][mA][mC][mC][mU][mG][mA][mG][m [mG][mG][mG] (SEQ ID NO 68) C][mU][mC][mU][mU][dT]*[dT] (SEQ ID
NO: 161) 05C47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] 05C475 [mC][mC][mC][mU][mC][mA][mG][mA][
6 [mG][mG][mU][mC][mU][mC][mU][mG][mA] -6 mG][mA][mC][mC][mU][mG][mA][mG][m [mG][mG][mG] (SEQ ID NO 69) C][mU][mC][mU][mU]
(SEQ ID NO: 162) 05C47A- [mA] [mA][mG] [mA] [mG] [mC] [mU][mC] [mA] 05C475 CCCUCAGAGACCUGAGCUCUU[dT]*[dT]
7 [mG][mG][mU][mC][mU][mC][mU][mG][mA] -7 (SEQ ID NO:
163) [mG][mG][mG][dT]*[dT] (SEQ ID NO 70) 05C47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] 05C475 [2fC][mC][2fC][mU][2fC][mA][2fG][mA][2 8 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] -8 fG][mA][2fC][mC][2fU][mG][2fA][mG][2f [mG][2fG][mG][dT]*[dT] (SEQ ID NO 71) C][mU][2fC][mU][2fU][dT]*[dT] (SEQ ID
NO: 164) 05C47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] 05C475 [2fC][mC][2fC][mU][2fC][mA][2fG][mA][2 9 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] -9 fG][mA][2fC][mC][2fU][mG][2fA][mG][2f [mG][2fG][mG] (SEQ ID NO 72) C][mU][2fC][mU][2fU][dT]*[dT] (SEQ ID
NO: 165) 05C47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] 05C475 [2fC][mC][2fC][mU][2fC][mA][2fG][mA][2 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] -10 fG][mA][2fC][mC][2fU][mG][2fA][mG][2f [mG][2fG][mG][dT]*[dT] (SEQ ID NO 73) C][mU][2fC][mU][2fU]
(SEQ ID NO: 166) 05C47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] 05C475 [2fC][mC][2fC][mU][2fC][mA][2fG]][mA][
11 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] -11 2fG
[mA] [2fC] [mC][2fU][mG] [2fA] [mG] [2f [mG][2fG][mG] (SEQ ID NO 74) C][mU][2fC][mU][2fU]
(SEQ ID NO: 167) 05C47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 12 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -12 [mC][2fC][mC][2fU][mC][2fA][mG][2fA][
[2fG][mG][2fG][dT]*[dT] (SEQ ID NO 75) mG][2fA][mC][2fC][mU][2fG][mA][2fG][m OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') C][2fU][mC][2fU][mU][dT][dT]* (SEQ ID
NO: 168) 05C47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 13 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -13 [2fC][mC][2fC][mU][2fC][mA][2fG][mA][2 [2fG][mG][2fG] (SEQ ID NO 76) fG][mA][2fC][mC][2fU][mG][2fA][mG][2f C][mU][2fC][mU][2fU]-LIG-LINKER (SEQ
ID NO: 169) 05C47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 14 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -14 [2fC][mC][2fC][mU][2fC][mA][2fG][mA][2 [2fG][mG][2fG] (SEQ ID NO 77) fG][mA][2fC][mC][2fU][mG][2fA][mG][2f C][mU][2fC][mU][2fU][dT]*[dT] (SEQ ID
NO: 170) 05C47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 15 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -15 [2fG][mA][2fG][mA][2fC][mC][2fU][mG][
[2fG][mG][2fG][dT]*[dT] (SEQ ID NO 78) 2fA][mG][2fC][mU][2fC][mU][2fU][dT]*[d T] (SEQ ID NO: 171) 05C47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 [2fG][mA][2fG][mA][2fC][mC][2fU][mG][
16 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -16 2fA][mG][2fC][mU][2fC][mU][2fU][dT]*[d [2fG][mG][2fG][dT]*[dT] (SEQ ID NO 79) T] (SEQ ID NO: 172) 05C47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 17 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] -17 [2fG][mA][2fG][mA][2fC][mC][2fU][mG][
[2fG][mG][2fG][dT]*[dT] (SEQ ID NO 80) 2fA][mG][2fC][mU][2fC][mU][2fU] (SEQ
ID NO: 173) 05C47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] 05C475 [2fG][mA][2fG][mA][2fC][mC][2fU][mG][
18 [mG][2fG][mU][2fC][mU][2fC][2fU][2fG][2fA] -18 2fA][mG][2fC][mU][2fC][mU][2fU] (SEQ
[2fG][2fG][2fG] (SEQ ID NO 81) ID NO: 174) 05C48A AAGAGCUCAGGUCUCUGAGGG[dT][dT] (SEQ 05C485 CCCUCAGAGACCUGAGCUCUU[dT][dT]
ID NO 82) (SEQ ID NO: 175) 05C49A AGAAGAGCUCAGGUCUCUGAG[dT][dT] (SEQ 05C495 CUCAGAGACCUGAGCUCUUCU[dT][dT]
ID NO: 83) (SEQ ID NO: 176) OSC50A AUAGGGAGUGUCCAGGGACCC[dT][dT] (SEQ 05C505 GGGUCCCUGGACACUCCCUAU[dT][dT]
ID NO: 84) (SEQ ID NO: 177) OSC51A UCCAUAGGGAGUGUCCAGGGA[dT][dT] (SEQ 05C515 UCCCUGGACACUCCCUAUGGA[dT][dT]
ID NO: 85) (SEQ ID NO: 178) 05C52A AUCUCCAUAGGGAGUGUCCAG[dT][dT] (SEQ 05C525 CUGGACACUCCCUAUGGAGAU[dT][dT]
ID NO: 86) (SEQ ID NO: 179) 05C53A UCAGUUCUGGCUGUGGCAGGU[dT][dT] (SEQ 05C535 ACCUGCCACAGCCAGAACUGA[dT][dT]
ID NO: 87) (SEQ ID NO: 180) 05C54A UUCUACCCCCUGGGAGCUGCC[dT][dT] (SEQ 05C545 GGCAGCUCCCAGGGGGUAGAA[dT][dT]
ID NO: 88) (SEQ ID NO: 181) 05C55A AAGCACAGGGCCGUUCUACCC[dT][dT] (SEQ 05C555 GGGUAGAACGGCCCUGUGCUU[dT][dT]
ID NO: 89) (SEQ ID NO: 182) OS ID Antisense Strand (5' TO 3') OSID Sense Strand (5' TO 3') 05C56A UG UCUUAAGCACAGGGCCGU U [dT] [dT] (SEQ 05C565 AACGGCCCUGUGCU
UAAGACA[dT][dT]
ID NO: 90) (SEQ ID NO: 183) 05C58A UU U UU UGAGGAUGUGAAGCAA[dT] [dT] 05C585 UUGCU
UCACAUCCUCAAAAAA[dT][dT]
(SEQ ID NO: 92) (SEQ ID NO: 185) OS ID Antisense Strand (5' TO 3') OS ID Sense Strand (5' TO
3') AAUAAAUAACCAACAGUUGGG[dThdT] (SEQ ID NO: 213) 051_275 CCCAACUGUUGGUUAUUUAUU[dThdT] (SEQ ID NO: 587) 05L44A UUUAAAUACUGAACUACUGUG[dT][dT] (SEQ ID NO: 230) 051_445 CACAGUAGUUCAGUAUUUAAA[dT][dT] (SEQ ID NO: 604) 05L82A AAUCUAUUGCAAUAGUUUCAG[dT][dT] (SEQ ID NO: 268) 051_825 CUGAAACUAUUGCAAUAGAUU[dT][dT] (SEQ ID NO: 642) 05L123A AUUGAAACAACAAUGAAAGAG[di][dT] (SEQ ID NO: 309) 051_1235 CUCUUUCAUUGUUGUUUCAAU [dll[dT] (SEQ ID NO: 683) OSL141A UUUUCAAAUUCCUAUCUACCC[dT][dT] (SEQ ID NO: 327) 051_1415 GGGUAGAUAGGAAUUUGAAAA[dT][dT] (SEQ ID NO: 701) 05L197A AAUCCAAUACAAUCUCUUCUC[dT][dT] (SEQ ID NO: 383) 051_1975 GAGAAGAGAUUGUAUUGGAUU[dT][dT] (SEQ ID NO: 757) 05L209A ACACAAUGUCCACUUGUACAC[dT][dT] (SEQ ID NO: 395) 051_2095 GUGUACAAGUGGACAUUGUGU[dT][dT] (SEQ ID NO: 769) 05L217A UAUUCUGUACAAGGUUUAGGG[dTlidT] (SEQ ID NO: 403) 051_2175 CCCUAAACCUUGUACAGAAUA[dT][dT] (SEQ ID NO: 777) 05L297A AUUUUAUAGGAAAUAUGAGUG[dTlidT] (SEQ ID NO: 517) 051_2975 CACUCAUAUUUCCUAUAAAAU[dT][dT] (SEQ ID NO: 891) 05L324A UAUAAAUGUACACAUUUAGCC[dThdT] (SEQ ID NO: 544) 0513245 GGCUAAAUGUGUACAUUUAUA[dT][dT] (SEQ ID NO: 918) OS ID Antisense Strand (5' TO 3') OS ID Sense Strand (5' TO 3') UACUU UGUGAGCAAUCUUGAC[dT] [dT] GUCAAGAU
UGCUCACAAAGUA[dT] [dT]
OSL1A (SEQ ID NO: 187) OSL1S (SEQ ID NO:
561) AU UCACUUGGGAUACACUGAC[dT] [dT]
GUCAGUGUAUCCCAAGUGAAU[dT][dT]
OSL2A (SEQ ID NO: 188) 05L25 (SEQ ID NO:
562) ACAUGAAAACUCAUUGUGCAA[dT][dT] UUGCACAAUGAGUUU
UCAUGU [dT] [dT]
OSL3A (SEQ ID NO: 189) 05L35 (SEQ ID NO:
563) UCU UUACAGUCAUCUUCUCCA[dT][dT] UGGAGAAGAUGACUG
UAAAGAUA[dT] [d OSL4A (SEQ ID NO: 190) 05L45 T] (SEQ ID NO:
564) UAUCU U UACAGUCAUCU UCUC[dT] [dT]
GAGAAGAUGACUGUAAAGAUA[dT][dT]
OSL5A (SEQ ID NO: 191) 05L55 (SEQ ID NO:
565) AACAUU UAUGAACAUCAUGAG [dT] [dT] CUCAUGAUGU UCAUAAAUGU
U[dT] [dT]
OSL6A (SEQ ID NO: 192) 05L65 (SEQ ID NO:
566) UCACAAACUU UAUAAAUGGAG [dT] [dT] CUCCAU UUAUAAAGUU UG
UGA[dT] [dT]
OSL7A (SEQ ID NO: 193) 05L75 (SEQ ID NO:
567) AU CACAAACU UUAUAAAUGGA[dT] [dT]
UCCAUUUAUAAAGUUUGUGAU[dT][dT]
OSL8A (SEQ ID NO: 194) 05L85 (SEQ ID NO:
568) AUACUACAGUAUU UUCCGGUA[dT] [dT]
UACCGGAAAAUACUGUAGUAU[dT][dT]
OSL9A (SEQ ID NO: 195) 05L95 (SEQ ID NO:
569) OSL10 UCAUACUACAGUAUUUUCCGG[dT][dT]
CCGGAAAAUACUGUAGUAUGA[dT][dT]
A (SEQ ID NO: 196) OSL1OS (SEQ ID NO: 570) OSL11 ACAAAUUCCCCAUAUCUGGCA[dT][dT] (SEQ
UGCCAGAUAUGGGGAAUUUGU[dT][dT]
A ID NO: 197) OSL11S (SEQ ID NO: 571) 05L12 AAGAUAUACCCUUCUUCACAG[dT][dT] (SEQ
CUGUGAAGAAGGGUAUAUCUU[dT][dT]
A ID NO: 198) 051_125 (SEQ ID NO: 572) 05L13 UUAGCUUUGCAAUACUGUCCA[dT][dT]
UGGACAGUAUUGCAAAGCUAA[dT][dT]
A (SEQ ID NO: 199) 05L135 (SEQ ID NO: 573) 05L14 AUCAUUAGCUUUGCAAUACUG[dT][dT]
CAGUAUUGCAAAGCUAAUGAU[dT][dT]
A (SEQ ID NO: 200) 051_145 (SEQ ID NO: 574) 05L15 AAAGGAAUCAUUAGCUUUGCA[dT][dT]
UGCAAAGCUAAUGAUUCCUUU[dT][dT]
A (SEQ ID NO: 201) 051_155 (SEQ ID NO: 575) 05L16 AUGAAUAUCACCAAUUAACAA[dT][dT] (SEQ
UUGUUAAUUGGUGAUAUUCAU[dT][dT]
A ID NO: 202) 051_165 (SEQ ID NO: 576) 05L17 AAAAAACCUUAUUUUGCACGG[dT][dT]
CCGUGCAAAAUAAGGUUUUUU[dT][dT]
A (SEQ ID NO: 203) 051_175 (SEQ ID NO: 577) 05L18 UGAAAAAACCUUAUUUUGCAC[dT][dT]
GUGCAAAAUAAGGUUUUUUCA[dT][dT]
A (SEQ ID NO: 204) 051_185 (SEQ ID NO: 578) 05L19 AAUGUCAACUGAAAAAACCUU[dT][dT] (SEQ
AAGGUUUUUUCAGUUGACAUU[dT][dT]
A ID NO: 205) 051_195 (SEQ ID NO: 579) 05L20 UAAUGUCAACUGAAAAAACCU[dT][dT] (SEQ
AGGUUUUUUCAGUUGACAUUA[dT][dT]
A ID NO: 206) 051_205 (SEQ ID NO: 580) 05L21 UUAAACCAUUAAUGUCAACUG[dT][dT]
CAGUUGACAUUAAUGGUUUAA[dT][dT]
A (SEQ ID NO: 207) 051_215 (SEQ ID NO: 581) 05L22 UAUUUAAACCAUUAAUGUCAA[dT][dT]
UUGACAUUAAUGGUUUAAAUA[dT][dT]
A (SEQ ID NO: 208) 051_225 (SEQ ID NO: 582) 05L23 UAGAUUUUAUUAUUAACCCAG[dT][dT]
CUGGGUUAAUAAUAAAAUCUA[dT][dT]
A (SEQ ID NO: 209) 051_235 (SEQ ID NO: 583) 05L24 AUAGAUUUUAUUAUUAACCCA[dT][dT]
UGGGUUAAUAAUAAAAUCUAU[dT][dT]
A (SEQ ID NO: 210) 051_245 (SEQ ID NO: 584) 05L25 AAAUUUACCAUAUCUAUGCGG[dT][dT]
CCGCAUAGAUAUGGUAAAUUU[dT][dT]
A (SEQ ID NO: 211) 051_255 (SEQ ID NO: 585) 05L26 AAGUUUUCAGUUAUAAGGGUA[dT][dT]
UACCCUUAUAACUGAAAACUU[dT][dT]
A (SEQ ID NO: 212) 051_265 (SEQ ID NO: 586) 05L27 AAUAAAUAACCAACAGUUGGG[dT][dT]
CCCAACUGUUGGUUAUUUAUU[dT][dT]
A (SEQ ID NO: 213) 051_275 (SEQ ID NO: 587) 05L28 AGAAAAAUAAAUAACCAACAG[dT][dT] (SEQ
CUGUUGGUUAUUUAUUUUUCU[dT][dT]
A ID NO: 214) 051_285 (SEQ ID NO: 588) 05L29 AUAUCAUAUCCAGAGUUACCC[dT][dT] (SEQ
GGGUAACUCUGGAUAUGAUAU[dT][dT]
A ID NO: 215) 051_295 (SEQ ID NO: 589) OSL30 AGUUUCAAUGUAAUCAAACCG[dT][dT]
CGGUUUGAUUACAUUGAAACU[dT][dT]
A (SEQ ID NO: 216) 051_305 (SEQ ID NO: 590) 05L31 UUACAGUUUCAAUGUAAUCAA[dT][dT]
UUGAUUACAUUGAAACUGUAA[dT][dT]
A (SEQ ID NO: 217) 051_315 (SEQ ID NO: 591) 05L32 AUAAGUUACAGUUUCAAUGUA[dT][dT]
UACAUUGAAACUGUAACUUAU[dT][dT]
A (SEQ ID NO: 218) 051_325 (SEQ ID NO: 592) 05L33 UCUUUACACGGAUUGGUAGCA[dT][dT]
UGCUACCAAUCCGUGUAAAGA[dT][dT]
A (SEQ ID NO: 219) 051_335 (SEQ ID NO: 593) 05L34 AAAAUCAAUCCCGACAAAGAA[dT][dT] (SEQ
UUCUUUGUCGGGAUUGAUUUU[dT][dT]
A ID NO: 220) 051_345 (SEQ ID NO: 594) 05L35 UCUGAAAAAAAGAUAGUGCUG[dT][dT]
CAGCACUAUCUUUUUUUCAGA[dT][dT]
A (SEQ ID NO: 221) 051_355 (SEQ ID NO: 595) 05L36 AUCUGAAAAAAAGAUAGUGCU[dT][dT]
AGCACUAUCUUUUUUUCAGAU[dT][dT]
A (SEQ ID NO: 222) 051_365 (SEQ ID NO: 596) 05L37 AAAAAUCAUGUGUUUUGACAU[dT][dT]
AUGUCAAAACACAUGAUUUUU[dT][dT]
A (SEQ ID NO: 223) 051_375 (SEQ ID NO: 597) 05L38 UUUGCUUAAAAAUCAUGUGUU[dT][dT]
AACACAUGAUUUUUAAGCAAA[dT][dT]
A (SEQ ID NO: 224) 051_385 (SEQ ID NO: 598) 05L39 AACUUUCAACAUUUUCCACCC[dT][dT] (SEQ
GGGUGGAAAAUGUUGAAAGUU[dT][dT]
A ID NO: 225) 051_395 (SEQ ID NO: 599) 05L40 UUGAAAUCCAAUCAAAAGCCA[dT][dT] (SEQ
UGGCUUUUGAUUGGAUUUCAA[dT][dT]
A ID NO: 226) 051_405 (SEQ ID NO: 600) 05L41 UUUGAAAUCCAAUCAAAAGCC[dT][dT] (SEQ
GGCUUUUGAUUGGAUUUCAAA[dT][dT]
A ID NO: 227) 051_415 (SEQ ID NO: 601) 05L42 UAGAGAUUCUUUGAAAUCCAA[dT][dT]
UUGGAUUUCAAAGAAUCUCUA[dT][dT]
A (SEQ ID NO: 228) 051_425 (SEQ ID NO: 602) 05L43 AUAGAGAUUCUUUGAAAUCCA[dT][dT]
UGGAUUUCAAAGAAUCUCUAU[dT][dT]
A (SEQ ID NO: 229) 051_435 (SEQ ID NO: 603) 05L44 UUUAAAUACUGAACUACUGUG[dT][dT]
CACAGUAGUUCAGUAUUUAAA[dT][dT]
A (SEQID NO: 230) 051_445 (SEQ ID NO: 604) 05L45 UAUUUAAAUACUGAACUACUG[dT][dT]
CAGUAGUUCAGUAUUUAAAUA[dT][dT]
A (SEQ ID NO: 231) 051_455 (SEQ ID NO: 605) 05L46 AUAGAUACCCGGCAAAAGGAU[dT][dT] (SEQ
AUCCUUUUGCCGGGUAUCUAU[dT][dT]
A ID NO: 232) 051_465 (SEQ ID NO: 606) 05L47 AAGAGUAGUGUUUAUUACAGG[dT][dT]
CCCCUGUAAUAAACACUACUC[dT][dT]
A (SEQ ID NO: 233) 051_475 (SEQ ID NO: 607) 05L48 AUCAAAAUAGGCAUCUACCCA[dT][dT] (SEQ
UGGGUAGAUGCCUAUUUUGAU[dT][dT]
A ID NO: 234) 051_485 (SEQ ID NO: 608) 05L49 UCAAUUUUAUCAAAAUAGGCA[dT][dT]
UGCCUAUUUUGAUAAAAUUGA[dT][dT]
A (SEQ ID NO: 235) 051_495 (SEQ ID NO: 609) OSL50 UAAAUGCUCUCCAAAGAUGGC[dT][dT]
GCCAUCUUUGGAGAGCAUUUA[dT][dT]
A (SEQ ID NO: 236) 051_505 (SEQ ID NO: 610) 05L51 UCAAAUGCAGUAUGUAAGCAA[dT][dT]
UUGCUUACAUACUGCAUUUGA[dT][dT]
A (SEQ ID NO: 237) 051_515 (SEQ ID NO: 611) 05L52 UUCAAAUGCAGUAUGUAAGCA[dT][dT]
UGCUUACAUACUGCAUUUGAA[dT][dT]
A (SEQ ID NO: 238) 051_525 (SEQ ID NO: 612) 05L53 UGAUUACAGGCGUUAGAACCA[dT][dT]
UGGUUCUAACGCCUGUAAUCA[dT][dT]
A (SEQ ID NO: 239) 051_535 (SEQ ID NO: 613) 05L54 UGUUAUCAUGACAAUCAUCGA[dT][dT]
UCGAUGAUUGUCAUGAUAACA[dT][dT]
A (SEQID NO: 240) 051_545 (SEQ ID NO: 614) 05L55 UUAUCACAGGUGUAUUGGGUG[dT][dT]
CACCCAAUACACCUGUGAUAA[dT][dT]
A (SEQ ID NO: 241) 051_555 (SEQ ID NO: 615) 05L56 AUUAUCACAGGUGUAUUGGGU[dT][dT]
ACCCAAUACACCUGUGAUAAU[dT][dT]
A (SEQ ID NO: 242) 051_565 (SEQ ID NO: 616) 05L57 AGUUCUUUGAGAUACACUGGU[dT][dT]
ACCAGUGUAUCUCAAAGAACU[dT][dT]
A (SEQ ID NO: 243) 051_575 (SEQ ID NO: 617) 05L58 UCGAAUUGCAGUUCUUUUCAU[dT][dT]
AUGAAAAGAACUGCAAUUCGA[dT][dT]
A (SEQ ID NO: 244) 051_585 (SEQ ID NO: 618) 05L59 UCAAUACAUCGAUGAUUGGGG[dT][dT]
CCCCAAUCAUCGAUGUAUUGA[dT][dT]
A (SEQ ID NO: 245) 051_595 (SEQ ID NO: 619) 05L60 AACGAUAGGUCAAUACAUCGA[dT][dT] (SEQ
UCGAUGUAUUGACCUAUCGUU[dT][dT]
A ID NO: 246) 051_605 (SEQ ID NO: 620) 05L61 ACAAACGAUAGGUCAAUACAU[dT][dT] (SEQ
AUGUAUUGACCUAUCGUUUGU[dT][dT]
A ID NO: 247) 051_615 (SEQ ID NO: 621) 05L62 UCAAAAACACCAUCACAACGA[dT][dT] (SEQ
UCGUUGUGAUGGUGUUUUUGA[dT][dT]
A ID NO: 248) 051_625 (SEQ ID NO: 622) 05L63 UCACAUUCCCAGAAGUUCGGG[dT][dT]
CCCGAACUUCUGGGAAUGUGA[dT][dT]
A (SEQ ID NO: 249) 051_635 (SEQ ID NO: 623) 05L64 AUCACAUUCCCAGAAGUUCGG[dT][dT] (SEQ
CCGAACUUCUGGGAAUGUGAU[dT][dT]
A ID NO: 250) 051_645 (SEQ ID NO: 624) 05L65 UGAUGAAGGGCAAGUCUUGGG[dT][dT]
CCCAAGACUUGCCCUUCAUCA[dT][dT]
A (SEQ ID NO: 251) 051_655 (SEQ ID NO: 625) 05L66 AGAAUCAUUGGCAAGUAAGAA[dT][dT]
UUCUUACUUGCCAAUGAUUCU[dT][dT]
A (SEQ ID NO: 252) 051_665 (SEQ ID NO: 626) 05L67 UAUCACAUUCAUCUAUGUCUU[dT][dT]
AAGACAUAGAUGAAUGUGAUA[dT][dT]
A (SEQ ID NO: 253) 051_675 (SEQ ID NO: 627) 05L68 AAUAUCACAUUCAUCUAUGUC[dT][dT]
GACAUAGAUGAAUGUGAUAUU[dT][dT]
A (SEQ ID NO: 254) 051_685 (SEQ ID NO: 628) 05L69 AACAUGUAGCCUGUAUCACAC[dT][dT] (SEQ
GUGUGAUACAGGCUACAUGUU[dT][dT]
A ID NO: 255) 051_695 (SEQ ID NO: 629) OSL70 UCACUUUCUAACAUGUAGCCU[dT][dT]
AGGCUACAUGUUAGAAAGUGA[dT][dT]
A (SEQ ID NO: 256) 051_705 (SEQ ID NO: 630) 05L71 AUCACUUUCUAACAUGUAGCC[dT][dT] (SEQ
GGCUACAUGUUAGAAAGUGAU[dT][dT]
A ID NO: 257) 051_715 (SEQ ID NO: 631) 05L72 AAUGUAAGAACCAUUCUCGAC[dT][dT] (SEQ
GUCGAGAAUGGUUCUUACAUU[dT][dT]
A ID NO: 258) 051_725 (SEQ ID NO: 632) 05L73 UACAAUGUAAGAACCAUUCUC[dT][dT] (SEQ
GAGAAUGGUUCUUACAUUGUA[dT][dT]
A ID NO: 259) 051_735 (SEQ ID NO: 633) 05L74 AAAAUCAACAGCUACAAUGUA[dT][dT] (SEQ
UACAUUGUAGCUGUUGAUUUU[dT][dT]
A ID NO: 260) 051_745 (SEQ ID NO: 634) 05L75 AUUGAAUCAAAAUCAACAGCU[dT][dT] (SEQ
AGCUGUUGAUUUUGAUUCAAU[dT][dT]
A ID NO: 261) 051_755 (SEQ ID NO: 635) 05L76 UAAUUGAAUCAAAAUCAACAG[dT][dT] (SEQ
CUGUUGAUUUUGAUUCAAUUA[dT][dT]
A ID NO: 262) 051_765 (SEQ ID NO: 636) 05L77 AAGAUACGACCACUAAUUGAA[dT][dT] (SEQ
UUCAAUUAGUGGUCGUAUCUU[dT][dT]
A ID NO: 263) 051_775 (SEQ ID NO: 637) 05L78 AGUUUCAGUCAAGAUGAUGCU[dT][dT]
AGCAUCAUCUUGACUGAAACU[dT][dT]
A (SEQ ID NO: 264) 051_785 (SEQ ID NO: 638) 05L79 AAUAGUUUCAGUCAAGAUGAU[dT][dT]
AUCAUCUUGACUGAAACUAUU[dT][dT]
A (SEQ ID NO: 265) 051_795 (SEQ ID NO: 639) 05L80 UAUUGCAAUAGUUUCAGUCAA[dT][dT]
UUGACUGAAACUAUUGCAAUA[dT][dT]
A (SEQ ID NO: 266) 051_805 (SEQ ID NO: 640) 05L81 UCUAUUGCAAUAGUUUCAGUC[dT][dT]
GACUGAAACUAUUGCAAUAGA[dT][dT]
A (SEQ ID NO: 267) 051_815 (SEQ ID NO: 641) 05L82 AAUCUAUUGCAAUAGUUUCAG[dT][dT]
CUGAAACUAUUGCAAUAGAUU[dT][dT]
A (SEQ ID NO: 268) 051_825 (SEQ ID NO: 642) 05L83 AUUUUGGAGACUUCAAUUGUU[dT][dT]
AACAAUUGAAGUCUCCAAAAU[dT][dT]
A (SEQ ID NO: 269) 051_835 (SEQ ID NO: 643) 05L84 UUAGGUUUUUACUAAUCAGCA[dT][dT]
UGCUGAUUAGUAAAAACCUAA[dT][dT]
A (SEQ ID NO: 270) 051_845 (SEQ ID NO: 644) 05L85 UCAUUCUGGGAUCUAAUGCUA[dT][dT]
UAGCAUUAGAUCCCAGAAUGA[dT][dT]
A (SEQ ID NO: 271) 051_855 (SEQ ID NO: 645) 05L86 UUCAUUCUGGGAUCUAAUGCU[dT][dT]
AGCAUUAGAUCCCAGAAUGAA[dT][dT]
A (SEQ ID NO: 272) 051_865 (SEQ ID NO: 646) 05L87 AGUAGAUGCUCAUUCAUUCUG[dT][dT]
CAGAAUGAAUGAGCAUCUACU[dT][dT]
A (SEQ ID NO: 273) 051_875 (SEQ ID NO: 647) 05L88 AUUAUAAUCACAAAAGUCCAU[dT][dT] (SEQ
AUGGACUUUUGUGAUUAUAAU[dT][dT]
A ID NO: 274) 051_885 (SEQ ID NO: 648) 05L89 UCCAUUAUAAUCACAAAAGUC[dT][dT] (SEQ
GACUUUUGUGAUUAUAAUGGA[dT][dT]
A ID NO: 275) 051_895 (SEQ ID NO: 649) OSL90 UGCCGUAUAAUCAAAUCAC[dT][dT] (SEQ ID
GUGUGAUUUGAUUAUACGGCA[dT][dT]
A NO: 276) 05005 (SEQ ID NO: 650) 05L91 AUAUUAUACAUUACAACUGAC[dT][dT]
GUCAGUUGUAAUGUAUAAUAU[dT][dT]
A (SEQ ID NO: 277) 05015 (SEQ ID NO: 651) 05L92 AUUGAAUAUUAUACAUUACAA[dT][dT]
UUGUAAUGUAUAAUAUUCAAU[dT][dT]
A (SEQ ID NO: 278) 05025 (SEQ ID NO: 652) 05L93 AAUUUGGUUGUUUCGAAGGAU[dT][dT]
AUCCUUCGAAACAACCAAAUU[dT][dT]
A (SEQ ID NO: 279) 05035 (SEQ ID NO: 653) 05L94 ACGGAAUUUGGUUGUUUCGAA[dT][dT]
UUCGAAACAACCAAAUUCCGU[dT][dT]
A (SEQ ID NO: 280) 05045 (SEQ ID NO: 654) 05L95 UUACAGUUAUUAAGAAAGGUU[dT][dT]
AACCUUUCUUAAUAACUGUAA[dT][dT]
A (SEQ ID NO: 281) 05055 (SEQ ID NO: 655) 05L96 UCCAAAAAUUAUAUGUUGCCU[dT][dT]
AGGCAACAUAUAAUUUUUGGA[dT][dT]
A (SEQ ID NO: 282) 05065 (SEQ ID NO: 656) 05L97 UUCCAAAAAUUAUAUGUUGCC[dT][dT]
GGCAACAUAUAAUUUUUGGAA[dT][dT]
A (SEQ ID NO: 283) 05075 (SEQ ID NO: 657) 05L98 UCUAAACCAUUCUGUAUCCCU[dT][dT] (SEQ
AGGGAUACAGAAUGGUUUAGA[dT][dT]
A ID NO: 284) 05085 (SEQ ID NO: 658) 05L99 AUCUAAACCAUUCUGUAUCCC[dT][dT] (SEQ
GGGAUACAGAAUGGUUUAGAU[dT][dT]
A ID NO: 285) 05095 (SEQ ID NO: 659) 05L10 UUCAACAUCUAAACCAUUCUG[dT][dT] (SEQ 05L100 CAGAAUGGUUUAGAUGUUGAA[dT][dT]
OA ID NO: 286) 5 (SEQ ID NO: 660) 05L10 AUUUUCAACCCAAUAGAUGUA[dT][dT] 05L101 UACAUCUAUUGGGUUGAAAAU[dT][dT]
1A (SEQ ID NO: 287) 5 (SEQ ID NO: 661) 05L10 UAUAGAAGCAAAUACUGUCCU[dT][dT] 05L102 AGGACAGUAUUUGCUUCUAUA[dT][dT]
2A (SEQ ID NO: 288) 5 (SEQ ID NO: 662) 05L10 UAGAUAUAGAAGCAAAUACUG[dT][dT] 05L103 CAGUAUUUGCUUCUAUAUCUA[dT][dT]
3A (SEQ ID NO: 289) 5 (SEQ ID NO: 663) 05L10 UAAGGCCAGGUUCAUAGAAGG[dT][dT] 05L104 CCUUCUAUGAACCUGGCCU[dT][dT] (SEQ
4A (SEQ ID NO: 290) 5 ID NO: 664) 05L10 UCUUGAAAUCCAAUCUAAGGC[dT][dT] 05L105 GCCUUAGAUUGGAUUUCAAGA[dT][dT]
5A (SEQ ID NO: 291) 5 (SEQ ID NO: 665) 05L10 AUAAAGGUUUCUUGAAAUCCA[dT][dT] 05L106 UGGAUUUCAAGAAACCUUUAU[dT][dT]
6A (SEQ ID NO: 292) 5 (SEQ ID NO: 666) 05L10 UCAAAACCUCGAUUGACUGAG[dT][dT] 05L107 CUCAGUCAAUCGAGGUUUUGA[dT][dT]
7A (SEQ ID NO: 293) 5 (SEQ ID NO: 667) 05L10 UUCUGUAUCUGAUAUCUCCGU[dT][dT] 05L108 ACGGAGAUAUCAGAUACAGAA[dT][dT]
8A (SEQ ID NO: 294) 5 (SEQ ID NO: 668) 05L10 UUUCUGUAUCUGAUAUCUCCG[dT][dT] 05L109 CGGAGAUAUCAGAUACAGAAA[dT][dT]
9A (SEQ ID NO: 295) 5 (SEQ ID NO: 669) 05L11 UUUUUCUGUAUCUGAUAUCUC[dT][dT] 05L110 GAGAUAUCAGAUACAGAAAAA[dT][dT]
OA (SEQ ID NO: 296) 5 (SEQ ID NO: 670) 05L11 AUCAAUGUUUUUCUGUAUCUG[dT][dT] 05L111 CAGAUACAGAAAAACAUUGAU[dT][dT]
1A (SEQ ID NO: 297) 5 (SEQ ID NO: 671) 05L11 AUAAAGGAAAGAAUCAUGGAC[dT][dT] 05L112 GUCCAUGAUUCUUUCCUUUAU[dT][dT]
2A (SEQ ID NO: 298) 5 (SEQ ID NO: 672) 05L11 AAUAAAGGAAAGAAUCAUGGA[dT][dT] 05L113 UCCAUGAUUCUUUCCUUUAUU[dT][dT]
3A (SEQ ID NO: 299) 5 (SEQ ID NO: 673) 05L11 UCAGUAUAAUAAAGGAAAGAA[dT][dT] 05L114 UUCUUUCCUUUAUUAUACUGA[dT][dT]
4A (SEQ ID NO: 300) 5 (SEQ ID NO: 674) 05L11 UUUCAAUGACCUCAUACUGUU[dT][dT] 05L115 AACAGUAUGAGGUCAUUGAAA[dT][dT]
5A (SEQ ID NO: 301) 5 (SEQ ID NO: 675) 05L11 AUUUGGAACAUUAUCUCUCAA[dT][dT] 05L116 UUGAGAGAUAAUGUUCCAAAU[dT][dT]
6A (SEQ ID NO: 302) 5 (SEQ ID NO: 676) 05L11 AGAUUUGGAACAUUAUCUCUC[dT][dT] 05L117 GAGAGAUAAUGUUCCAAAUCU[dT][dT]
7A (SEQ ID NO: 303) 5 (SEQ ID NO: 677) 05L11 UCAGAUUUGGAACAUUAUCUC[dT][dT] 05L118 GAGAUAAUGUUCCAAAUCUGA[dT][dT]
8A (SEQ ID NO: 304) 5 (SEQ ID NO: 678) 05L11 UUGCUACAGCCAUUUGAGG[dT][dT] (SEQ 05L119 CCUCAAAUGGCUGUAGCAA[dT][dT] (SEQ
9A ID NO: 305) 5 ID NO: 679) 05L12 AUGAAAGAGUUAUAUGGAGAG[dT][dT] 05L120 CUCUCCAUAUAACUCUUUCAU[dT][dT]
OA (SEQ ID NO: 306) 5 (SEQ ID NO: 680) 05L12 ACAAUGAAAGAGUUAUAUGGA[dT][dT] 05L121 UCCAUAUAACUCUUUCAUUGU[dT][dT]
1A (SEQ ID NO: 307) 5 (SEQ ID NO: 681) 05L12 UGAAACAACAAUGAAAGAGUU[dT][dT] 05L122 AACUCUUUCAUUGUUGUUUCA[dT][dT]
2A (SEQ ID NO: 308) 5 (SEQ ID NO: 682) 05L12 AUUGAAACAACAAUGAAAGAG[dT][dT] 05L123 CUCUUUCAUUGUUGUUUCAAU
[dT][dT]
3A (SEQ ID NO: 309) 5 (SEQ ID NO: 683) 05L12 AGCUAAAGCCUCUGAUUGCAG[dT][dT] 05L124 CUGCAAUCAGAGGCUUUAGCU[dT][dT]
4A (SEQ ID NO: 310) 5 (SEQ ID NO: 684) 05L12 AAGCUAAAGCCUCUGAUUGCA[dT][dT] 05L125 UGCAAUCAGAGGCUUUAGCUU[dT][dT]
5A (SEQ ID NO: 311) 5 (SEQ ID NO: 685) 05L12 ACAAUUCCAAGCUAAAGCCUC[dT][dT] (SEQ 05L126 GAGGCUUUAGCUUGGAAUUGU[dT][dT]
6A ID NO: 312) 5 (SEQ ID NO: 686) 05L12 UGACAAUUCCAAGCUAAAGCC[dT][dT] (SEQ 05L127 GGCUUUAGCUUGGAAUUGUCA[dT][dT]
7A ID NO: 313) 5 (SEQ ID NO: 687) 05L12 UGAAUGAUCUGACAAUUCCAA[dT][dT] 05L128 UUGGAAUUGUCAGAUCAUUCA[dT][dT]
8A (SEQ ID NO: 314) 5 (SEQ ID NO: 688) 05L12 AUGUUCAUCAGAGAAGAUCCA[dT][dT] 05L129 UGGAUCUUCUCUGAUGAACAU[dT][dT]
9A (SEQ ID NO: 315) 5 (SEQ ID NO: 689) 05L13 UAUUCCAUGUGUCACAAUGUU[dT][dT] OSL130 AACAUUGUGACACAUGGAAUA[dT][dT]
OA (SEQ ID NO: 316) 5 (SEQ ID NO: 690) 05L13 ACUUCUAUCAGUGUUUCAGAA[dT][dT] 05L131 UUCUGAAACACUGAUAGAAGU[dT][dT]
1A (SEQ ID NO: 317) 5 (SEQ ID NO: 691) 05L13 UAUUGAUCCGCAGAACUUCUA[dT][dT] 05L132 UAGAAGUUCUGCGGAUCAAUA[dT][dT]
2A (SEQ ID NO: 318) 5 (SEQ ID NO: 692) 05L13 UGUUCUUGGGAUCUACAACAA[dT][dT] 05L133 UUGUUGUAGAUCCCAAGAACA[dT][dT]
3A (SEQ ID NO: 319) 5 (SEQ ID NO: 693) 05L13 AAAGAACGCUCAAUCUUUGGU[dT][dT] 05L134 ACCAAAGAUUGAGCGUUCUUU[dT][dT]
4A (SEQ ID NO: 320) 5 (SEQ ID NO: 694) 05L13 UAAACGUAGCCAUCACUUCGG[dT][dT] (SEQ 05L135 CCGAAGUGAUGGCUACGUUUA[dT][dT]
5A ID NO: 321) 5 (SEQ ID NO: 695) 05L13 AUCUAAAGAAUCAUCAACCCA[dT][dT] (SEQ 05L136 UGGGUUGAUGAUUCUUUAGAU[dT][dT]
6A ID NO: 322) 5 (SEQ ID NO: 696) 05L13 UUAUAUCUAAAGAAUCAUCAA[dT][dT] 05L137 UUGAUGAUUCUUUAGAUAUAA[dT][dT]
7A (SEQ ID NO: 323) 5 (SEQ ID NO: 697) 05L13 AUAGAAUUUUCAAAAACAGUG[dT][dT] 05L138 CACUGUUUUUGAAAAUUCUAU[dT][dT]
8A (SEQ ID NO: 324) 5 (SEQ ID NO: 698) 05L13 UGAUAGAAUUUUCAAAAACAG[dT][dT] 05L139 CUGUUUUUGAAAAUUCUAUCA[dT][dT]
9A (SEQ ID NO: 325) 5 (SEQ ID NO: 699) 05L14 UUUCAAAUUCCUAUCUACCCA[dT][dT] (SEQ 05L140 UGGGUAGAUAGGAAUUUGAAA[dT][dT]
OA ID NO: 326) 5 (SEQ ID NO: 700) 05L14 UUUUCAAAUUCCUAUCUACCC[dT][dT] (SEQ 05L141 GGGUAGAUAGGAAUUUGAAAA[dT][dT]
1A ID NO: 327) 5 (SEQ ID NO: 701) 05L14 AUAUUGUCUCUUAUCACUGUG[dT][dT] 05L142 CACAGUGAUAAGAGACAAUAU[dT][dT]
2A (SEQ ID NO: 328) 5 (SEQ ID NO: 702) 05L14 UGAUAUUGUCUCUUAUCACUG[dT][dT] 05L143 CAGUGAUAAGAGACAAUAUCA[dT][dT]
3A (SEQ ID NO: 329) 5 (SEQ ID NO: 703) 05L14 UGAAAUGGCACAAUUCUUGCC[dT][dT] 05L144 GGCAAGAAUUGUGCCAUUUCA[dT][dT]
4A (SEQ ID NO: 330) 5 (SEQ ID NO: 704) 05L14 UGUUGAAAUGGCACAAUUCUU[dT][dT] 05L145 AAGAAUUGUGCCAUUUCAACA[dT][dT]
5A (SEQ ID NO: 331) 5 (SEQ ID NO: 705) 05L14 AAUUUUCUGUUGAAAUGGCAC[dT][dT] 05L146 GUGCCAUUUCAACAGAAAAUU[dT][dT]
6A (SEQ ID NO: 332) 5 (SEQ ID NO: 706) 05L14 AAAUUUUCUGUUGAAAUGGCA[dT][dT] 05L147 UGCCAUUUCAACAGAAAAUUU[dT][dT]
7A (SEQ ID NO: 333) 5 (SEQ ID NO: 707) 05L14 AUUAGACAAGGCAAAGAUGAG[dT][dT] 05L148 CUCAUCUUUGCCUUGUCUAAU[dT][dT]
8A (SEQ ID NO: 334) 5 (SEQ ID NO: 708) 05L14 ACAUUUAUUGUUUGGAAAGGU[dT][dT] 05L149 ACCUUUCCAAACAAUAAAUGU[dT][dT]
9A (SEQ ID NO: 335) 5 (SEQ ID NO: 709) 05L15 AUCACUUACACUGUCAUAGUC[dT][dT] (SEQ 05L150 GACUAUGACAGUGUAAGUGAU[dT][dT]
OA ID NO: 336) 5 (SEQ ID NO: 710) 05L15 UAGAUUCUAUCACUUACACUG[dT][dT] 05L151 CAGUGUAAGUGAUAGAAUCUA[dT][dT]
1A (SEQ ID NO: 337) 5 (SEQ ID NO: 711) 05L15 AGUAGAUUCUAUCACUUACAC[dT][dT] 05L152 GUGUAAGUGAUAGAAUCUACU[dT][dT]
2A (SEQ ID NO: 338) 5 (SEQ ID NO: 712) 05L15 UUUUGUGUGAAGUAGAUUCUA[dT][dT] 05L153 UAGAAUCUACUUCACACAAAA[dT][dT]
3A (SEQ ID NO: 339) 5 (SEQ ID NO: 713) 05L15 UAAAUUUUGUGUGAAGUAGAU[dT][dT] 05L154 AUCUACUUCACACAAAAUUUA[dT][dT]
4A (SEQ ID NO: 340) 5 (SEQ ID NO: 714) 05L15 UCUAGUAAUCCAGUCAAAGGC[dT][dT] 05L155 GCCUUUGACUGGAUUACUAGA[dT][dT]
5A (SEQ ID NO: 341) 5 (SEQ ID NO: 715) 05L15 AAUUCUUCUAGUAAUCCAGUC[dT][dT] 05L156 GACUGGAUUACUAGAAGAAUU[dT][dT]
6A (SEQ ID NO: 342) 5 (SEQ ID NO: 716) 05L15 UAAAUUCUUCUAGUAAUCCAG[dT][dT] 05L157 CUGGAUUACUAGAAGAAUUUA[dT][dT]
7A (SEQ ID NO: 343) 5 (SEQ ID NO: 717) 05L15 AUAAAUUCUUCUAGUAAUCCA[dT][dT] 05L158 UGGAUUACUAGAAGAAUUUAU[dT][dT]
8A (SEQ ID NO: 344) 5 (SEQ ID NO: 718) 05L15 AUAUACUGGCCAUAGAGAGUC[dT][dT] 05L159 GACUCUCUAUGGCCAGUAUAU[dT][dT]
9A (SEQ ID NO: 345) 5 (SEQ ID NO: 719) 05L16 UUCUU UGUGUGUACAAGUCAG [dT] [dT] 05L160 CUGACUUGUACACACAAAGAA[dT][dT]
OA (SEQ ID NO: 346) 5 (SEQ ID NO: 720) 05L16 AAUUCUUUGUGUGUACAAGUC[dT][dT] 05L161 GACUUGUACACACAAAGAAUU[dT][dT]
1A (SEQ ID NO: 347) 5 (SEQ ID NO: 721) 05L16 UCGGUAAAUUCUUUGUGUGUA[dT][dT] 05L162 UACACACAAAGAAUUUACCGA[dT][dT]
2A (SEQ ID NO: 348) 5 (SEQ ID NO: 722) 05L16 UGUUACACUGUUGUUUCUGGU[dT][dT] 05L163 ACCAGAAACAACAGUGUAACA[dT][dT]
3A (SEQ ID NO: 349) 5 (SEQ ID NO: 723) 05L16 AUUGUUACACUGUUGUUUCUG[dT][dT] 05L164 CAGAAACAACAGUGUAACAAU[dT][dT]
4A (SEQ ID NO: 350) 5 (SEQ ID NO: 724) 05L16 AAACUGUUCACAAGGAUUGUU[dT][dT] 05L165 AACAAUCCUUGUGAACAGUUU[dT][dT]
5A (SEQ ID NO: 351) 5 (SEQ ID NO: 725) 05L16 ACAUCGUUCACCAUUGUCCAC[dT][dT] (SEQ 05L166 GUGGACAAUGGUGAACGAUGU[dT][dT]
6A ID NO: 352) 5 (SEQ ID NO: 726) 05L16 UGUUAUUGCACAUAAACUCCG[dT][dT] 05L167 CGGAGUUUAUGUGCAAUAACA[dT][dT]
7A (SEQ ID NO: 353) 5 (SEQ ID NO: 727) 05L16 UCUGUUAUUGCACAUAAACUC[dT][dT] 05L168 GAGUUUAUGUGCAAUAACAGA[dT][dT]
8A (SEQ ID NO: 354) 5 (SEQ ID NO: 728) 05L16 UUAUGACAUUUUGUGUAUCCA[dT][dT] 05L169 UGGAUACACAAAAUGUCAUAA[dT][dT]
9A (SEQ ID NO: 355) 5 (SEQ ID NO: 729) 05L17 UGAAUUAUGACAUUUUGUGUA[dT][dT] OSL170 UACACAAAAUGUCAUAAUUCA[dT][dT]
OA (SEQ ID NO: 356) 5 (SEQ ID NO: 730) 05L17 UUUGAAUUAUGACAUU UUGUG [dT][dT] 05L171 CACAAAAUGUCAUAAUUCAAA[dT][dT]
1A (SEQ ID NO: 357) 5 (SEQ ID NO: 731) 05L17 UACAAAUAUUUGAAUUAUGAC[dT][dT] 05L172 GUCAUAAUUCAAAUAUUUGUA[dT][dT]
2A (SEQ ID NO: 358) 5 (SEQ ID NO: 732) 05L17 AAAUAAACGCGAGGAAUACAA[dT][dT] (SEQ 05L173 UUGUAUUCCUCGCGUUUAUUU[dT][dT]
3A ID NO: 359) 5 (SEQ ID NO: 733) 05L17 AAUAAGUAGGGUUUUCAUCAC[dT][dT] 05L174 GUGAUGAAAACCCUACUUAUU[dT][dT]
4A (SEQ ID NO: 360) 5 (SEQ ID NO: 734) 05L17 UCACAAUACCAAUGUUGAGGA[dT][dT] 05L175 UCCUCAACAUUGGUAUUGUGA[dT][dT]
5A (SEQ ID NO: 361) 5 (SEQ ID NO: 735) 05L17 UGUUUCUUGAUCACAAUACCA[dT][dT] 05L176 UGGUAUUGUGAUCAAGAAACA[dT][dT]
6A (SEQ ID NO: 362) 5 (SEQ ID NO: 736) 05L17 AACAAUCUGUUUCUUGAUCAC[dT][dT] 05L177 GUGAUCAAGAAACAGAUUGUU[dT][dT]
7A (SEQ ID NO: 363) 5 (SEQ ID NO: 737) 05L17 UUUACACAGAGAAACUCGGAA[dT][dT] (SEQ 05L178 UUCCGAGUUUCUCUGUGUAAA[dT][dT]
8A ID NO: 364) 5 (SEQ ID NO: 738) 05L17 AUUUACACAGAGAAACUCGGA[dT][dT] (SEQ 05L179 UCCGAGUUUCUCUGUGUAAAU[dT][dT]
9A ID NO: 365) 5 (SEQ ID NO: 739) 05L18 UUCUGAUUCUCAUCGUAGCCG[dT][dT] 05L180 CGGCUACGAUGAGAAUCAGAA[dT][dT]
OA (SEQ ID NO: 366) 5 (SEQ ID NO: 740) 05L18 AUUUUCAGAGCAAGUUCUCCU[dT][dT] 05L181 AGGAGAACUUGCUCUGAAAAU[dT][dT]
1A (SEQ ID NO: 367) 5 (SEQ ID NO: 741) 05L18 AUAUCUUUGGGAUACACAGUC[dT][dT] 05L182 GACUGUGUAUCCCAAAGAUAU[dT][dT]
2A (SEQ ID NO: 368) 5 (SEQ ID NO: 742) 05L18 AGGUAAACUGAUUCUGUUGGC[dT][dT] 05L183 GCCAACAGAAUCAGUUUACCU[dT][dT]
3A (SEQ ID NO: 369) 5 (SEQ ID NO: 743) 05L18 AUAGAAACUGGUUAAGGUGUC[dT][dT] 05L184 GACACCUUAACCAGUUUCUAU[dT][dT]
4A (SEQ ID NO: 370) 5 (SEQ ID NO: 744) 05L18 ACAAUAGAAACUGGUUAAGGU[dT][dT] 05L185 ACCUUAACCAGUUUCUAUUGU[dT][dT]
5A (SEQ ID NO: 371) 5 (SEQ ID NO: 745) 05L18 UCAUCAAUAUCAACACAAGUC[dT][dT] (SEQ 05L186 GACUUGUGUUGAUAUUGAUGA[dT][dT]
6A ID NO: 372) 5 (SEQ ID NO: 746) 05L18 AGAUGUAGGAGCCUAUUACAU[dT][dT] 05L187 AUGUAAUAGGCUCCUACAUCU[dT][dT]
7A (SEQ ID NO: 373) 5 (SEQ ID NO: 747) 05L18 UCGAUGUUACUGUUUUGCCGG[dT][dT] 05L188 CCGGCAAAACAGUAACAUCGA[dT][dT]
8A (SEQ ID NO: 374) 5 (SEQ ID NO: 748) 05L18 UUGCUAAAAAUGAGAUAGGGU[dT][dT] 05L189 ACCCUAUCUCAUUUUUAGCAA[dT][dT]
9A (SEQ ID NO: 375) 5 (SEQ ID NO: 749) 05L19 AUUUCUCAAAUAGUAACGGUU[dT][dT] OSL190 AACCGUUACUAUUUGAGAAAU[dT][dT]
OA (SEQ ID NO: 376) 5 (SEQ ID NO: 750) 05L19 AAUUUCUCAAAUAGUAACGGU[dT][dT] 05L191 ACCGUUACUAUUUGAGAAAUU[dT][dT]
1A (SEQ ID NO: 377) 5 (SEQ ID NO: 751) 05L19 AAAUUUCUCAAAUAGUAACGG[dT][dT] 05L192 CCGUUACUAUUUGAGAAAUUU[dT][dT]
2A (SEQ ID NO: 378) 5 (SEQ ID NO: 752) 05L19 AGUUAAAUUUCUCAAAUAGUA[dT][dT] 05L193 UACUAUUUGAGAAAUUUAACU[dT][dT]
3A (SEQ ID NO: 379) 5 (SEQ ID NO: 753) 05L19 AUCUAUAGUUAAAUUUCUCAA[dT][dT] 05L194 UUGAGAAAUUUAACUAUAGAU[dT][dT]
4A (SEQ ID NO: 380) 5 (SEQ ID NO: 754) 05L19 UAAAAAUAGCCAUCUAUAGUU[dT][dT] 05L195 AACUAUAGAUGGCUAUUUUUA[dT][dT]
5A (SEQ ID NO: 381) 5 (SEQ ID NO: 755) 05L19 AUCUAAUGCCACAACAUUGUC[dT][dT] (SEQ 05L196 GACAAUGUUGUGGCAUUAGAU[dT][dT]
6A ID NO: 382) 5 (SEQ ID NO: 756) 05L19 AAUCCAAUACAAUCUCUUCUC[dT][dT] (SEQ 05L197 GAGAAGAGAUUGUAUUGGAUU[dT][dT]
7A ID NO: 383) 5 (SEQ ID NO: 757) 05L19 ACAUUCUCUCAAUGACUUGCC[dT][dT] (SEQ 05L198 GGCAAGUCAUUGAGAGAAUGU[dT][dT]
8A ID NO: 384) 5 (SEQ ID NO: 758) 05L19 AUGAUUGUCUCCUUGUUUGUC[dT][dT] 05L199 GACAAACAAGGAGACAAUCAU[dT][dT]
9A (SEQ ID NO: 385) 5 (SEQ ID NO: 759) 05L20 AUUAUCACAGACUUGUUGGUU[dT][dT] 05L200 AACCAACAAGUCUGUGAUAAU[dT][dT]
OA (SEQ ID NO: 386) 5 (SEQ ID NO: 760) 05L20 UUCAAAAAUGGUAAUAGCGAA[dT][dT] 05L201 UUCGCUAUUACCAUUUUUGAA[dT][dT]
1A (SEQ ID NO: 387) 5 (SEQ ID NO: 761) 05L20 UCUUCAAAAAUGGUAAUAGCG[dT][dT] 05L202 CGCUAUUACCAUUUUUGAAGA[dT][dT]
2A (SEQ ID NO: 388) 5 (SEQ ID NO: 762) 05L20 AUUUGUUUCCCUUUUCCACUG[dT][dT] 05L203 CAGUGGAAAAGGGAAACAAAU[dT][dT]
3A (SEQ ID NO: 389) 5 (SEQ ID NO: 763) 05L20 AUUUGAUCCAUCAUAUUUGUU[dT][dT] 05L204 AACAAAUAUGAUGGAUCAAAU[dT][dT]
4A (SEQ ID NO: 390) 5 (SEQ ID NO: 764) 05L20 UAUAUGGAUGGUACACAUGGA[dT][dT] 05L205 UCCAUGUGUACCAUCCAUAUA[dT][dT]
5A (SEQ ID NO: 391) 5 (SEQ ID NO: 765) 05L20 AAAGAAGACGGUCUUCAUCAG[dT][dT] 05L206 CUGAUGAAGACCGUCUUCUUU[dT][dT]
6A (SEQ ID NO: 392) 5 (SEQ ID NO: 766) 05L20 UGAAUUCUGUGAAGUUGUCAC[dT][dT] 05L207 GUGACAACUUCACAGAAUUCA[dT][dT]
7A (SEQ ID NO: 393) 5 (SEQ ID NO: 767) 05L20 ACAAUGUCCACUUGUACACUG[dT][dT] (SEQ 05L208 CGGUGUACAAGUGGACAUUGU[dT][dT]
8A ID NO: 394) 5 (SEQ ID NO: 768) 05L20 ACACAAUGUCCACUUGUACAC[dT][dT] (SEQ 05L209 GUGUACAAGUGGACAUUGUGU[dT][dT]
9A ID NO: 395) 5 (SEQ ID NO: 769) 05L21 UUUUUGCAUUCGAACAUAGUA[dT][dT] 05L210 UACUAUGUUCGAAUGCAAAAA[dT][dT]
OA (SEQ ID NO: 396) 5 (SEQ ID NO: 770) 05L21 AUGGUUUUUGCAUUCGAACAU[dT][dT] 05L211 AUGUUCGAAUGCAAAAACCAU[dT][dT]
1A (SEQ ID NO: 397) 5 (SEQ ID NO: 771) 05L21 AUACAAACAUGGUUUUUGCAU[dT][dT] 05L212 AUGCAAAAACCAUGUUUGUAU[dT][dT]
2A (SEQ ID NO: 398) 5 (SEQ ID NO: 772) 05L21 AUCACAUUUCCAAUAUGGCGG[dT][dT] 05L213 CCGCCAUAUUGGAAAUGUGAU[dT][dT]
3A (SEQ ID NO: 399) 5 (SEQ ID NO: 773) 05L21 UGAAGUUCUUCAUCUGAACCA[dT][dT] 05L214 UGGUUCAGAUGAAGAACUUCA[dT][dT]
4A (SEQ ID NO: 400) 5 (SEQ ID NO: 774) 05L21 AUAAAUGCAGCGAUUGUUGUC[dT][dT] 05L215 GACAACAAUCGCUGCAUUUAU[dT][dT]
5A (SEQ ID NO: 401) 5 (SEQ ID NO: 775) 05L21 AUUCUGUACAAGGUUUAGGGG[dT][dT] 05L216 CCCCUAAACCUUGUACAGAAU[dT][dT]
6A (SEQ ID NO: 402) 5 (SEQ ID NO: 776) 05L21 UAUUCUGUACAAGGUUUAGGG[dT][dT] 05L217 CCCUAAACCUUGUACAGAAUA[dT][dT]
7A (SEQ ID NO: 403) 5 (SEQ ID NO: 777) 05L21 AUUCAUAUUCUGUACAAGGUU[dT][dT] 05L218 AACCUUGUACAGAAUAUGAAU[dT][dT]
8A (SEQ ID NO: 404) 5 (SEQ ID NO: 778) 05L21 UAUUCAUAUUCUGUACAAGGU[dT][dT] 05L219 ACCUUGUACAGAAUAUGAAUA[dT][dT]
9A (SEQ ID NO: 405) 5 (SEQ ID NO: 779) 05L22 UUAUAUUCAUAUUCUGUACAA[dT][dT] 05L220 UUGUACAGAAUAUGAAUAUAA[dT][dT]
OA (SEQ ID NO: 406) 5 (SEQ ID NO: 780) 05L22 UAUUGCAACCCAGUUCAUCGG[dT][dT] 05L221 CCGAUGAACUGGGUUGCAAUA[dT][dT]
1A (SEQ ID NO: 407) 5 (SEQ ID NO: 781) 05L22 AUAUUUUCAGCACAUGUUCUU[dT][dT] 05L222 AAGAACAUGUGCUGAAAAUAU[dT][dT]
2A (SEQ ID NO: 408) 5 (SEQ ID NO: 782) 05L22 UUAAUUGGGUACAAUUUUGCU[dT][dT] 05L223 AGCAAAAUUGUACCCAAUUAA[dT][dT]
3A (SEQ ID NO: 409) 5 (SEQ ID NO: 783) 05L22 AAAAACAUUGGUUUCGAACCC[dT][dT] (SEQ 05L224 GGGUUCGAAACCAAUGUUUUU[dT][dT]
4A ID NO: 410) 5 (SEQ ID NO: 784) 05L22 UGUCAAAAACAUUGGUUUCGA[dT][dT] 05L225 UCGAAACCAAUGUUUUUGACA[dT][dT]
5A (SEQ ID NO: 411) 5 (SEQ ID NO: 785) 05L22 UUCGAAUUCGGACAUUGUCAG[dT][dT] 05L226 CUGACAAUGUCCGAAUUCGAA[dT][dT]
6A (SEQ ID NO: 412) 5 (SEQ ID NO: 786) 05L22 AUUAUAUUUUCGAAUUCGGAC[dT][dT] 05L227 GUCCGAAUUCGAAAAUAUAAU[dT][dT]
7A (SEQ ID NO: 413) 5 (SEQ ID NO: 787) 05L22 AGAUUAUAUUUUCGAAUUCGG[dT][dT] 05L228 CCGAAUUCGAAAAUAUAAUCU[dT][dT]
8A (SEQ ID NO: 414) 5 (SEQ ID NO: 788) 05L22 UCAUCUUGAAGAUACUCUGAG[dT][dT] 05L229 CUCAGAGUAUCUUCAAGAUGA[dT][dT]
9A (SEQ ID NO: 415) 5 (SEQ ID NO: 789) 05L23 UAUAUUCCUCAUCUUGAAGAU[dT] [dT] 05L230 AUCUUCAAGAUGAGGAAUAUA[dT][dT]
OA (SEQ ID NO: 416) 5 (SEQ ID NO: 790) 05L23 UUUGAUAGCACCAAACCUAGAGCCC[dT] [dT 05L231 GGGCUCUAGGUUUGGUGCUAUCAAA[dT
1A-1 ] (SEQ ID NO: 417) 5-1 ][dT] (SEQ ID NO:
791) 05L23 UUUGAUAGCACCAAACCUAGAGCCC[dT]*[d 05L231 GGGCUCUAGGUUUGGUGCUAUCAAA[dT
1A-2 T] (SEQ ID NO: 418) 5-2 ]*[dT] (SEQ ID NO:
792) [mU][mU][mU][mG][mA][mU][mA][mG][m [mG][mG][mG][mC][mU][mC][mU][mA][
C][mA][mC][mC][mA][mA][mA][mC][mC][m mG][mG][mU][mU][mU][mG][mG][mU][
05L23 U][mA][mG][mA][mG][mC][mC][mC][dT]*[d 05L231 mG][mC][mU][mA][mU][mC][mA][mA][
1A-3 T] (SEQ ID NO: 419) 5-3 mA][dT]*[dT] (SEQ ID
NO: 793) [mU][mU][mU][mG][mA][mU][mA][mG][m [mG][mG][mG][mC][mU][mC][mU][mA][
C][mA][mC][mC][mA][mA][mA][mC][mC][m mG][mG][mU][mU][mU][mG][mG][mU][
05L23 U][mA][mG][mA][mG][mC][mC][mC][dT]*[d 05L231 mG][mC][mU][mA][mU][mC][mA][mA][
1A-4 T] (SEQ ID NO: 420) 5-4 mA] (SEQ ID NO: 794) [mU][mU][mU][mG][mA][mU][mA][mG][m C][mA][mC][mC][mA][mA][mA][mC][mC][m [mG][mG][mG][mC][mU][mC][mU][mA][
U][mA][mG][mA][mG][mC][mC][mC] (SEQ
mG][mG][mU][mU][mU][mG][mG][mU][
05L23 ID NO: 421) 05L231 mG][mC][mU][mA][mU][mC][mA][mA][
1A-5 5-5 mA][dT]*[dT] (SEQ ID
NO: 795) [mU][mU][mU][mG][mA][mU][mA][mG][m [mG][mG][mG][mC][mU][mC][mU][mA][
C][mA][mC][mC][mA][mA][mA][mC][mC][m mG][mG][mU][mU][mU][mG][mG][mU][
05L23 U][mA][mG][mA][mG][mC][mC][mC] (SEQ 05L231 mG][mC][mU][mA][mU][mC][mA][mA][
1A-6 ID NO: 422) 5-6 mA] (SEQ ID NO: 796) [mU][mU][mU][mG][mA][mU][mA][mG][m GGGCUCUAGGUUUGGUGCUAUCAAA[dT
C][mA][mC][mC][mA][mA][mA][mC][mC][m ]*[dT] (SEQ ID NO:
797) 05L23 U][mA][mG][mA][mG][mC][mC][mC][dT]*[d 05L231 1A-7 T] (SEQ ID NO: 423) 5-7 [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m [2fG][mG][2fG][mC][2fU][mC][2fU][mA][
C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f 2fG][mG][2fU][mU][2fU][mG][2fG][mU][
05L23 U][mA][2fG][mA][2fG][mC][2fC][mC][dT]*[ 05L231 2fG][mC][2fU][mA][2fU][mC][2fA][mA][2 1A-8 dT] (SEQ ID NO: 424) 5-8 fA][dT]*[dT] (SEQ ID
NO: 798) [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m [2fG][mG][2fG][mC][2fU][mC][2fU][mA][
C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f 2fG][mG][2fU][mU][2fU][mG][2fG][mU][
05L23 U][mA][2fG][mA][2fG][mC][2fC][mC] (SEQ 05L231 2fG][mC][2fU][mA][2fU][mC][2fA][mA][2 1A-9 ID NO: 425) 5-9 fA][dT]*[dT] (SEQ ID
NO: 799) [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f [2fG][mG][2fG][mC][2fU][mC][2fU][mA][
U][mA][2fG][mA][2fG][mC][2fC][mC][dT]*[
2fG][mG][2fU][mU][2fU][mG][2fG][mU][
05L23 dT] (SEQ ID NO: 426) 05L231 2fG][mC][2fU][mA][2fU][mC][2fA][mA][2 1A-10 S-W fA] (SEQ ID NO: 800) [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m [2fG][mG][2fG][mC][2fU][mC][2fU][mA][
C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f 2fG][mG][2fU][mU][2fU][mG][2fG][mU][
05L23 U][mA][2fG][mA][2fC][mC][2fC][mC] (SEQ 05L231 2fG][mC][2fU][mA][2fU][mC][2fA][mA][2 1A-11 ID NO: 427) 5-11 fA] (SEQ ID NO: 801) [2fU][mU][2fU][mG][2fA][mU][2fA][mG][2f [mG][2fG][mG][2fC][mU][2fC][mU][2fA][
C][mA][2fC][mC][2fA][mA][2fA][mC][2fC][m mG][2fG][mU][2fU][mU][2fG][mG][2Fu][
05L23 U][2fA][mG][2fA][mG][2fC][mC][2fC][dT]*[ 05L231 mG][2fC][mU][2fA][mU][2fC][mA][2fA][
1A-12 dT] (SEQ ID NO: 428) S-12 mA][dT]*[dT] (SEQ ID
NO: 802) [mU][2fA][mU][2fC][mA][2fA][mA][2fC][mC
[2fG][mG][2fG][mC][2fU][mC][2fU][mA][
][2fU][mC][2fG][mA][2fU][mA][2fG][mC][2f 2fG][mG][2fU][mU][2fU][mG][2fG][mU][
05L23 A][mA][2fC][mA][2fC][mC][2fG][mC] (SEQ 05L231 2fG][mC][2fU][mA][2fU][mC][2fA][mA][2 1A-13 ID NO: 429) S-13 fALINKER-LIG (SEQ ID
NO: 803) [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG][2f C][2fA][2fC][2fC][2fA][2fA][2fA][2fC][2fC][2f [2fU][mC][2fU][mA][2fG][mG][2fU][mU][
U][2fA][2fG][2fA][2fG][2fC][2fC][2fC][dT]*[
2fU][mG][2fG][mU][2fG][mC][2fU][mA][
05L23 dT] (SEQ ID NO: 430) 05L231 2fU][mC][2fA][mA][2fA][dT]*[dT] (SEQ
1A-14 S-14 ID NO: 804) [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG][2f C][2fA][2fC][2fC][2fA][2fA][2fA][2fC][2fC][2f [2fU][mU][2fU][mG][2fG][mU][2fG][mC][
05L23 U][2fA][2fG][2fA][2fG][2fC][2fC][2fC][dT]*[ 05L231 2fU][mA][2fU][mC][2fA][mA][2fA][dT]*[
1A-15 dT] (SEQ ID NO: 431) 5-15 dT] (SEQ ID NO: 805) [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f [2fU][mU][2fU][mG][2fG][mU][2fG][mC][
05L23 U][mA][2fG][mA][2fG][mC][2fC][mC][dT]*[ 05L231 2fU][mA][2fU][mC][2fA][mA][2fA][dT]*[
1A-16 dT] (SEQ ID NO: 432) S-16 dT] (SEQ ID NO: 806) [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m [2fU][mU][2fU][mG][2fG][mU][2fG][mC][
C][2fA][mC][2fC][mA][2fA][mA][2fC][mC][2f 2fU][mA][2fU][mC][2fA][mA][2fA] (SEQ
05L23 U][mA][2fG][mA][2fG][mC] (SEQ ID NO: 05L231 ID NO:
807) 1A-17 433) S-17 [mU][2fU][mU][2fG][mA][2fU][mA][2fG][m [2fU][mU][2fU][mG][2fG][mU][2fG][mC][
C][2fA][mC][2fC][mA][2fA][mA][2fC][2fC] [2f 2fU][mA][2fU][mC][2fA][mA][2fA] (SEQ
05L23 U][2fA][2fG][2fA][2fG][2fC] (SEQ ID NO: 05L231 ID NO:
808) 1A-18 434) S-18 05L23 UCAAAGUUGGGGAUGUAGGCA[dT][dT] 05L232 UGCCUACAUCCCCAACUUUGA[dT][dT]
2A (SEQ ID NO: 435) 5 (SEQ ID NO: 809) 05L23 UCAGUUUCAGGUCAACUUCCU[dT][dT] 05L233 AGGAAGUUGACCUGAAACUGA[dT][dT]
3A (SEQ ID NO: 436) 5 (SEQ ID NO: 810) 05L23 UACGUAUUUCAGUUUCAGGUC[dT][dT] 05L234 GACCUGAAACUGAAAUACGUA[dT][dT]
4A (SEQ ID NO: 437) 5 (SEQ ID NO: 811) 05L23 UUACGUAUUUCAGUUUCAGGU[dT][dT] 05L235 ACCUGAAACUGAAAUACGUAA[dT][dT]
5A (SEQ ID NO: 438) 5 (SEQ ID NO: 812) 05L23 AGUUUAGCCACCUCAAUGCGU[dT][dT] 05L236 ACGCAUUGAGGUGGCUAAACU[dT][dT]
6A (SEQ ID NO: 439) 5 (SEQ ID NO: 813) 05L23 AACAUAAGCCCUAGUUUGGGA[dT][dT] 05L237 UCCCAAACUAGGGCUUAUGUU[dT][dT]
7A (SEQ ID NO: 440) 5 (SEQ ID NO: 814) 05L23 UCGAUUUUAGGUUCCUUUCCC[dT][dT] 05L238 GGGAAAGGAACCUAAAAUCGA[dT][dT]
8A (SEQ ID NO: 441) 5 (SEQ ID NO: 815) 05L23 UCGAAAACCAGGAUGUUGCGG[dT][dT] 05L239 CCGCAACAUCCUGGUUUUCGA[dT][dT]
9A (SEQ ID NO: 442) 5 (SEQ ID NO: 816) 05L24 UCAAAUAAUCGAUAGAAAGGC[dT][dT] 05L240 GCCUUUCUAUCGAUUAUUUGA[dT][dT]
OA (SEQ ID NO: 443) 5 (SEQ ID NO: 817) 05L24 UUGUUCAAAUAAUCGAUAGAA[dT][dT] 05L241 UUCUAUCGAUUAUUUGAACAA[dT][dT]
1A (SEQ ID NO: 444) 5 (SEQ ID NO: 818) 05L24 UUAUGGUUUCAAUAACGUCCU[dT][dT] 05L242 AGGACGUUAUUGAAACCAUAA[dT][dT]
2A (SEQ ID NO: 445) 5 (SEQ ID NO: 819) 05L24 UUUUAUGGUUUCAAUAACGUC[dT][dT] 05L243 GACGUUAUUGAAACCAUAAAA[dT][dT]
3A (SEQ ID NO: 446) 5 (SEQ ID NO: 820) 05L24 AUUUUAUGGUUUCAAUAACGU[dT][dT] 05L244 ACGUUAUUGAAACCAUAAAAU[dT][dT]
4A (SEQ ID NO: 447) 5 (SEQ ID NO: 821) 05L24 UUUGCAAUGACUCUCCUAUCAGUCC[dT][dT 05L245 GGACUGAUAGGAGAGUCAUUGCAAA[dT]
5A-1 ] (SEQ ID NO: 448) 5-1 [dT] (SEQ ID NO: 822) UUUGCAAUGACUCUCCUAUCAGUCC[dT]*[d 05L24 T] (SEQ ID NO: 449) 05L245 GGACUGAUAGGAGAGUCAUUGCAA]A[dT
5A-2 S-2 ]*[dT] (SEQ ID NO:
823) [mU][mU][mU][mG][mC][mA][mA][mU][m [mG][mG][mA][mC][mU][mG][mA][mU][
G][mA][mC][mU][mC][mU][mC][mC][mU][
mA][mG][mG][mA][mG][mA][mG][mU][
05L24 mA][mU][mC][mA][mG][mU][mC][mC][dT]* 05L245 mC][mA][mU][mU][mG][mC][mA][mA][
5A-3 [dT] (SEQ ID NO: 450) S-3 mA][dT]*[dT] (SEQ ID
NO: 824) [mU][mU][mU][mG][mC][mA][mA][mU][m G][mA][mC][mU][mC][mU][mC][mC][mU][
[mG][mG][mA][mC][mU][mG][mA][mU][
mA][mU][mC][mA][mG][mU][mC][mC][dT]*
mA][mG][mG][mA][mG][mA][mG][mU][
05L24 [dT] (SEQ ID NO: 451) 05L245 mC][mA][mU][mU][mG][mC][mA][mA][
5A-4 S-4 mA](SEQ ID NO: 825) [mU][mU][mU][mG][mC][mA][mA][mU][m [mG][mG][mA][mC][mU][mG][mA][mU][
G][mA][mC][mU][mC][mU][mC][mC][mU][
mA][mG][mG][mA][mG][mA][mG][mU][
05L24 mA][mU][mC][mA][mG][mU][mC][mC] (SEQ 05L245 mC][mA][mU][mU][mG][mC][mA][mA][
5A-5 ID NO: 452) 5-5 mA][dT]*[dT](SEQ ID
NO: 826) [mU][mU][mU][mG][mC][mA][mA][mU][m [mG][mG][mA][mC][mU][mG][mA][mU][
G][mA][mC][mU][mC][mU][mC][mC][mU][
mA][mG][mG][mA][mG][mA][mG][mU][
05L24 mA][mU][mC][mA][mG][mU][mC][mC] (SEQ 05L245 mC][mA][mU][mU][mG][mC][mA][mA][
5A-6 ID NO: 453) S-6 mA] (SEQ ID NO: 827) [mU][mU][mU][mG][mC][mA][mA][mU][m GGACUGAUAGGAGAGUCAUUGCAAA[dT]
G][mA][mC][mU][mC][mU][mC][mC][mU][ *[dT] (SEQ ID NO:
828) 05L24 mA][mU][mC][mA][mG][mU][mC][mC][dT]* 05L245 5A-7 [dT] (SEQ ID NO: 454) S-7 [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mG][2fA][mC][2fU][mG][2fA][mU][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fA][mG][2fG][mA][2fG][mA][2fG][mU][
05L24 fA][mU][2fC][mA][2fG][mU][2fC][mC][dT]*[ 05L245 2fC][mA][2fU][mU] [2fG][mC][2fA][mA] [2 5A-8 dT] (SEQ ID NO: 455) S-8 fA][dT]*[dT] (SEQ ID
NO: 829) [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mG][2fA][mC][2fU][mG][2fA][mU][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fA][mG][2fG][mA][2fG][mA][2fG][mU][
05L24 fA][mU][2fC][mA][2fG][mU][2fC][mC] (SEQ 05L245 2fC][mA][2fU][mU] [2fG][mC][2fA][mA] [2 5A-9 ID NO: 456) S-9 fA][dT]*[dT] (SEQ ID
NO: 830) [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mG][2fA][mC][2fU][mG][2fA][mU][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fA][mG][2fG][mA][2fG][mA][2fG][mU][
05L24 fA][mU][2fC][mA][2fG][mU][2fC][mC][dT]*[ 05L245 2fC][mA][2fU][mU] [2fG][mC][2fA][mA] [2 5A-10 dT] (SEQ ID NO: 457) S-W fA] (SEQ ID NO: 831) [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mG][2fA][mC][2fU][mG][2fA][mU][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fA][mG][2fG][mA][2fG][mA][2fG][mU][
05L24 fA][mU][2fC][mA][2fC][mU][2fC][mC] (SEQ 05L245 2fC][mA][2fU][mU] [2fG][mC][2fA][mA] [2 5A-11 ID NO: 458) 5-11 fA] (SEQ ID NO: 832) [2fU][mU][2fU][mG][2fC][mA][2fA][mU][2f [mG][2fG][mA][2fC][mU][2fG][mA][2fU][
G][mA][2fC][mU][2fC][mU][2fC][mC][2fU][
mA][2fG][mG][2fA][mG][2fA][mG][2fU][
05L24 mA][2fU][mC][2fA][mG][2fU][mC][2fC][dT]* 05L245 mC][2fA][mU][2fU][mG][2fC][mA][2fA][
5A-12 [dT] (SEQ ID NO: 459) S-12 mA][dT]*[dT] (SEQ ID
NO: 833) [mU][2fA][mU][2fC][mC][2fU][mA][2fA][mG
[2fG][mG][2fA][mC][2fU][mG][2fA][mU][
][2fU][mC][2fA][mC][2fA][mC][2fG][mU][2f 2fA][mG][2fG][mA][2fG][mA][2fG][mU][
05L24 U][mU][2fG][mA][2fC][mU][2fG][mC] (SEQ 05L245 2fC][mA][2fU][mU] [2fG][mC][2fA][mA] [2 5A-13 ID NO: 460) S-13 fA] (SEQ ID NO: 834) [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU][2f [2fU][mG][2fA][mU][2fA][mG][2fG][mA][
G][2fA][2fC][2fU][2fC][2fU][2fC][2fC][2fU][2 2fG][mA][2fG][mU][2fC][mA][2fU][mU][
05L24 fA][2fU][2fC][2fA][2fG][2fU][2fC][2fC][dT]*[ 05L245 2fG][mC][2fA][mA][2fA][dT]*[dT] (SEQ ID
5A-14 dT] (SEQ ID NO: 461) S-14 NO: 835) [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU][2f [2fG][mA][2fG][mA][2fG][mU][2fC][mA][
G][2fA][2fC][2fU][2fC][2fU][2fC][2fC][2fU][2 2fU][mU][2fG][mC][2fA][mA][2fA][dT]*[
05L24 fA][2fU][2fC][2fA][2fG][2fU][2fC][2fC][dT]*[ 05L245 dT]
(SEQ ID NO: 836) 5A-15 dT] (SEQ ID NO: 462) 5-15 [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mA][2fG][mA][2fG][mU][2fC][mA][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fU][mU][2fG][mC][2fA][mA][2fA][dT]*[
05L24 fA][mU][2fC][mA][2fG][mU][2fC][mC][dT]*[ 05L245 dT] (SEQ
ID NO: 837) 5A-16 dT] (SEQ ID NO: 463) S-16 [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m [2fG][mA][2fG][mA][2fG][mU][2fC][mA][
G][2fA][mC][2fU][mC][2fU][mC][2fC][mU][2 2fU][mU][2fG][mC][2fA][mA][2fA] (SEQ
05L24 fA][mU][2fC][mA][2fG][mU] (SEQ ID NO: 05L245 ID NO:
838) 5A-17 464) S-17 [mU][2fU][mU][2fG][mC][2fA][mA][2fU][m ACCAGUUAUACUGGAUAUCUA[dT][dT]
G][2fA][mC][2fU][mC][2fU][mC][2fC][2fU][2 (SEQ ID NO: 840) 05L24 fA][2fU][2fC][2fA][2fG][2fU] (SEQ ID NO: 05L245 5A-18 465) S-18 05L24 UAGAUAUCCAGUAUAACUGGU[dT][dT] 05L246 GGGAGAAGUAUGGAAACAAAA[dT][dT]
6A (SEQ ID NO: 466) 5 (SEQ ID NO: 841) 05L24 UUUUGUUUCCAUACUUCUCCC[dT][dT] 05L247 AAGUAUGGAAACAAAAUAAAU[dT][dT]
7A (SEQ ID NO: 467) 5 (SEQ ID NO: 842) 05L24 AUUUAUUUUGUUUCCAUACUU[dT][dT] 05L248 UUCAUCAACUCAGAUACAAUA[dT][dT]
8A (SEQ ID NO: 468) 5 (SEQ ID NO: 843) 05L24 UAUUGUAUCUGAGUUGAUGAA[dT][dT] 05L249 CGGAGGAAAUUGCUAUUUUGA[dT][dT]
9A (SEQ ID NO: 469) 5 (SEQ ID NO: 844) 05L25 UCAAAAUAGCAAUUUCCUCCG[dT][dT] (SEQ 05L250 AGGAAAUUGCUAUUUUGAUGA[dT][dT]
OA ID NO: 470) 5 (SEQ ID NO: 845) 05L25 UCAUCAAAAUAGCAAUUUCCU[dT][dT] (SEQ 05L251 CACCGGAAAAUAUUGUGAAAU[dT][dT]
1A ID NO: 471) 5 (SEQ ID NO: 846) 05L25 AUUUCACAAUAUUUUCCGGUG[dT][dT] 05L252 UUGUGAAAUGGCGUUUUCAAA[dT][dT]
2A (SEQ ID NO: 472) 5 (SEQ ID NO: 847) 05L25 UUUGAAAACGCCAUUUCACAA[dT][dT] (SEQ 05L253 CAGGAUUCUUCCACUAUAGAA[dT][dT]
3A ID NO: 473) 5 (SEQ ID NO: 848) 05L25 UUCUAUAGUGGAAGAAUCCUG[dT][dT] 05L254 GGCAGAUCUUAACAUGGAUAU[dT][dT]
4A (SEQ ID NO: 474) 5 (SEQ ID NO: 849) 05L25 AUAUCCAUGUUAAGAUCUGCC[dT][dT] 05L255 GGCAAUGAGUGAAGACUUUGU[dT][dT]
5A (SEQ ID NO: 475) 5 (SEQ ID NO: 850) 05L25 ACAAAGUCUUCACUCAUUGCC[dT][dT] (SEQ 05L256 AUCUGAAAAUGUGGAUAAUAA[dT][dT]
6A ID NO: 476) 5 (SEQ ID NO: 851) 05L25 UUAUUAUCCACAUUUUCAGAU[dT][dT] 05L257 ACCAGUUAUACUGGAUAUCUA[dT][dT]
7A (SEQ ID NO: 477) 5 (SEQ ID NO: 840) 05L25 UCUUAUUAUCCACAUUUUCAG[dT][dT] 05L258 CUGAAAAUGUGGAUAAUAAGA[dT][dT]
8A (SEQ ID NO: 478) 5 (SEQ ID NO: 852) 05L25 UCCAUAAUUCUUAUUAUCCAC[dT][dT] 05L259 GUGGAUAAUAAGAAUUAUGGA[dT][dT]
9A (SEQ ID NO: 479) 5 (SEQ ID NO: 853) 05L26 UUCCAUAAUUCUUAUUAUCCA[dT][dT] 05L260 UGGAUAAUAAGAAUUAUGGAA[dT][dT]
OA (SEQ ID NO: 480) 5 (SEQ ID NO: 854) 05L26 UUUUCGUUUGAAGAGAUUCCA[dT][dT] 05L261 UGGAAUCUCUUCAAACGAAAA[dT][dT]
1A (SEQ ID NO: 481) 5 (SEQ ID NO: 855) 05L26 UAGAUUUUCGUUUGAAGAGAU[dT][dT] 05L262 AUCUCUUCAAACGAAAAUCUA[dT][dT]
2A (SEQ ID NO: 482) 5 (SEQ ID NO: 856) 05L26 UUUAGAUUUUCGUUUGAAGAG[dT][dT] 05L263 CUCUUCAAACGAAAAUCUAAA[dT][dT]
3A (SEQ ID NO: 483) 5 (SEQ ID NO: 857) 05L26 UUGUUUAGAUUUUCGUUUGAA[dT][dT] 05L264 UUCAAACGAAAAUCUAAACAA[dT][dT]
4A (SEQ ID NO: 484) 5 (SEQ ID NO: 858) 05L26 UAGUUUGUUUAGAUUUUCGUU[dT][dT] 05L265 AACGAAAAUCUAAACAAACUA[dT][dT]
5A (SEQ ID NO: 485) 5 (SEQ ID NO: 859) 05L26 UUUCAAAGUUGGUAGUUUGUU[dT][dT] 05L266 AACAAACUACCAACUUUGAAA[dT][dT]
6A (SEQ ID NO: 486) 5 (SEQ ID NO: 860) 05L26 AUUGGAUUUUCAAAGUUGGUA[dT][dT] 05L267 UACCAACUUUGAAAAUCCAAU[dT][dT]
7A (SEQ ID NO: 487) 5 (SEQ ID NO: 861) 05L26 AUAGAUUGGAUUUUCAAAGUU[dT][dT] 05L268 AACUUUGAAAAUCCAAUCUAU
[dT][dT]
8A (SEQ ID NO: 488) 5 (SEQ ID NO: 862) 05L26 UUAAAAGUGUCUUCUGUUGCA[dT][dT] 05L269 UGCAACAGAAGACACUUUUAA[dT][dT]
9A (SEQ ID NO: 489) 5 (SEQ ID NO: 863) 05L27 UCUUUAACAAGAUUUGCGGUG[dT][dT] 05L270 CACCGCAAAUCUUGUUAAAGA[dT][dT]
OA (SEQ ID NO: 490) 5 (SEQ ID NO: 864) 05L27 UCUUCUUUAACAAGAUUUGCG[dT][dT] 05L271 CGCAAAUCUUGUUAAAGAAGA[dT][dT]
1A (SEQ ID NO: 491) 5 (SEQ ID NO: 865) 05L27 UGGUAUAGCUAUACUUCAGAG[dT][dT] 05L272 CUCUGAAGUAUAGCUAUACCA[dT][dT]
2A (SEQ ID NO: 492) 5 (SEQ ID NO: 866) 05L27 AUUAUUCCCUAAAUAGCUGGU[dT][dT] 05L273 ACCAGCUAUUUAGGGAAUAAU[dT][dT]
3A (SEQ ID NO: 493) 5 (SEQ ID NO: 867) 05L27 UAAUUAUUCCCUAAAUAGCUG[dT][dT] 05L274 CAGCUAUUUAGGGAAUAAUUA[dT][dT]
4A (SEQ ID NO: 494) 5 (SEQ ID NO: 868) 05L27 AUAUAUGUGCAAAAGUGUGUU[dT][dT] 05L275 AACACACUUUUGCACAUAUAU[dT][dT]
5A (SEQ ID NO: 495) 5 (SEQ ID NO: 869) 05L27 AAAUAUAUGUGCAAAAGUGUG[dT][dT] 05L276 CACACUUUUGCACAUAUAUUU[dT][dT]
6A (SEQ ID NO: 496) 5 (SEQ ID NO: 870) 05L27 AACUUUUUUCAUCUGUUUGUA[dT][dT] 05L277 UACAAACAGAUGAAAAAAGUU[dT][dT]
7A (SEQ ID NO: 497) 5 (SEQ ID NO: 871) 05L27 UAAAGUACUGAAUGUUAACUU[dT][dT] 05L278 AAGUUAACAUUCAGUACUUUA[dT][dT]
8A (SEQ ID NO: 498) 5 (SEQ ID NO: 872) 05L27 UUUUUUUCAUAAAGUACUGAA[dT][dT] 05L279 UUCAGUACUUUAUGAAAAAAA[dT][dT]
9A (SEQ ID NO: 499) 5 (SEQ ID NO: 873) 05L28 UAUUUUUUUCAUAAAGUACUG[dT][dT] 05L280 CAGUACUUUAUGAAAAAAAUA[dT][dT]
OA (SEQ ID NO: 500) 5 (SEQ ID NO: 874) 05L28 AUUUGUAAAAAUAUGAGACGG[dT][dT] 05L281 CCGUCUCAUAUUUUUACAAAU[dT][dT]
1A (SEQ ID NO: 501) 5 (SEQ ID NO: 875) 05L28 ACAUUGUGAUAAUUAUUUGUA[dT][dT] 05L282 UACAAAUAAUUAUCACAAUGU[dT][dT]
2A (SEQ ID NO: 502) 5 (SEQ ID NO: 876) 05L28 AUACAUAUAGUACAUUGUGAU[dT][dT] 05L283 AUCACAAUGUACUAUAUGUAU[dT][dT]
3A (SEQ ID NO: 503) 5 (SEQ ID NO: 877) 05L28 AUAUACAUAUAGUACAUUGUG[dT][dT] 05L284 CACAAUGUACUAUAUGUAUAU[dT][dT]
4A (SEQ ID NO: 504) 5 (SEQ ID NO: 878) 05L28 AAAGAUAUACAUAUAGUACAU[dT][dT] 05L285 AUGUACUAUAUGUAUAUCUUU[dT][dT]
5A (SEQ ID NO: 505) 5 (SEQ ID NO: 879) 05L28 AUUACCUUCAGACAACUUCAG[dT][dT] (SEQ 05L286 CUGAAGUUGUCUGAAGGUAAU[dT][dT]
6A ID NO: 506) 5 (SEQ ID NO: 880) 05L28 UAUUUAUAGUAUUACCUUCAG[dT][dT] 05L287 CUGAAGGUAAUACUAUAAAUA[dT][dT]
7A (SEQ ID NO: 507) 5 (SEQ ID NO: 881) 05L28 UAAUCUUUCCAAAAUUUACAA[dT][dT] 05L288 UUGUAAAUUUUGGAAAGAUUA[dT][dT]
8A (SEQ ID NO: 508) 5 (SEQ ID NO: 882) 05L28 AGUAACAGGAUAAUCUUUCCA[dT][dT] 05L289 UGGAAAGAUUAUCCUGUUACU[dT][dT]
9A (SEQ ID NO: 509) 5 (SEQ ID NO: 883) 05L29 AUUCAGUAACAGGAUAAUCUU[dT][dT] 05L290 AAGAUUAUCCUGUUACUGAAU[dT][dT]
OA (SEQ ID NO: 510) 5 (SEQ ID NO: 884) 05L29 UAGCAAAUUCAGUAACAGGAU[dT][dT] 05L291 AUCCUGUUACUGAAUUUGCUA[dT][dT]
1A (SEQ ID NO: 511) 5 (SEQ ID NO: 885) 05L29 UUAGCAAAUUCAGUAACAGGA[dT][dT] 05L292 UCCUGUUACUGAAUUUGCUAA[dT][dT]
2A (SEQ ID NO: 512) 5 (SEQ ID NO: 886) 05L29 UCUUUAUUAGCAAAUUCAGUA[dT][dT] 05L293 UACUGAAUUUGCUAAUAAAGA[dT][dT]
3A (SEQ ID NO: 513) 5 (SEQ ID NO: 887) 05L29 AUCAUUUACUAUAAUGAUCAC[dT][dT] 05L294 GUGAUCAUUAUAGUAAAUGAU[dT][dT]
4A (SEQ ID NO: 514) 5 (SEQ ID NO: 888) 05L29 UUCUUGUUGGAUCAUUUACUA[dT][dT] 05L295 UAGUAAAUGAUCCAACAAGAA[dT][dT]
5A (SEQ ID NO: 515) 5 (SEQ ID NO: 889) 05L29 UCAAUUCCUUUUCUUGUUGGA[dT][dT] 05L296 UCCAACAAGAAAAGGAAUUGA[dT][dT]
6A (SEQ ID NO: 516) 5 (SEQ ID NO: 890) 05L29 AUUUUAUAGGAAAUAUGAGUG[dT][dT] 05L297 CACUCAUAUUUCCUAUAAAAU[dT][dT]
7A (SEQ ID NO: 517) 5 (SEQ ID NO: 891) 05L29 UAAUUUUAUAGGAAAUAUGAG[dT][dT] 05L298 CUCAUAUUUCCUAUAAAAUUA[dT][dT]
8A (SEQ ID NO: 518) 5 (SEQ ID NO: 892) 05L29 UGCUAAUGUGUAAAAAUGGAC[dT][dT] 05L299 GUCCAUUUUUACACAUUAGCA[dT][dT]
9A (SEQ ID NO: 519) 5 (SEQ ID NO: 893) 05L30 UUGAACAUUAAUUAAGUGCUA[dT][dT] 05L300 UAGCACUUAAUUAAUGUUCAA[dT][dT]
OA (SEQ ID NO: 520) 5 (SEQ ID NO: 894) 05L30 AUUGAACAUUAAUUAAGUGCU[dT][dT] 05L301 AGCACUUAAUUAAUGUUCAAU[dT][dT]
1A (SEQ ID NO: 521) 5 (SEQ ID NO: 895) 05L30 AUAUUGAACAUUAAUUAAGUG[dT][dT] 05L302 CACUUAAUUAAUGUUCAAUAU[dT][dT]
2A (SEQ ID NO: 522) 5 (SEQ ID NO: 896) 05L30 AAAUUGACAUGUAAUAUUGAA[dT][dT] 05L303 UUCAAUAUUACAUGUCAAUUU[dT][dT]
3A (SEQ ID NO: 523) 5 (SEQ ID NO: 897) 05L30 AUCAACAUAGCCAUUAAUCAA[dT][dT] (SEQ 05L304 UUGAUUAAUGGCUAUGUUGAU[dT][dT]
4A ID NO: 524) 5 (SEQ ID NO: 898) 05L30 UCUAUACAACACAUAGUGGCC[dT][dT] (SEQ 05L305 GGCCACUAUGUGUUGUAUAGA[dT][dT]
5A ID NO: 525) 5 (SEQ ID NO: 899) 05L30 AUGUCUAUACAACACAUAGUG[dT][dT] 05L306 CACUAUGUGUUGUAUAGACAU[dT][dT]
6A (SEQ ID NO: 526) 5 (SEQ ID NO: 900) 05L30 ACUGAAUUGCUUUUCCUACCU[dT][dT] 05L307 AGGUAGGAAAAGCAAUUCAGU[dT][dT]
7A (SEQ ID NO: 527) 5 (SEQ ID NO: 901) OSL30 AAAUAAAAAUGUUGUCUUGGC[dT] [dT] 05L308 GCCAAGACAACAUUUUUAUUU[dT] [dT]
8A (SEQ ID NO: 528) 5 (SEQ ID NO: 902) 05L30 AUCACAAAUAAAAAUGUUGUC[dT][dT] 05L309 GACAACAUUUUUAUUUGUGAU[dT][dT]
9A (SEQ ID NO: 529) 5 (SEQ ID NO: 903) 05L31 AAUGAUAUGGGAUUUCCUCAU[dT][dT] 05L310 AUGAGGAAAUCCCAUAUCAUU[dT][dT]
OA (SEQ ID NO: 530) 5 (SEQ ID NO: 904) 05L31 AUUAACCACAAACUCAAUGCA[dT][dT] (SEQ 05L311 UGCAUUGAGUUUGUGGUUAAU[dT][dT]
1A ID NO: 531) 5 (SEQ ID NO: 905) 05L31 UUUAAUUAACCACAAACUCAA[dT][dT] (SEQ 05L312 UUGAGUUUGUGGUUAAUUAAA[dT][dT]
2A ID NO: 532) 5 (SEQ ID NO: 906) 05L31 UUUGGUUUCAGAAAUUCAGCU[dT][dT] 05L313 AGCUGAAUUUCUGAAACCAAA[dT][dT]
3A (SEQ ID NO: 533) 5 (SEQ ID NO: 907) 05L31 UUAUGAAGACACAGAUUUGGU[dT][dT] 05L314 ACCAAAUCUGUGUCUUCAUAA[dT][dT]
4A (SEQ ID NO: 534) 5 (SEQ ID NO: 908) 05L31 UUUCAUAGAAACAAAAACCCA[dT][dT] (SEQ 05L315 UGGGUUUUUGUUUCUAUGAAA[dT][dT]
5A ID NO: 535) 5 (SEQ ID NO: 909) 05L31 AUGAUAUUUUCAUAGAAACAA[dT][dT] 05L316 UUGUUUCUAUGAAAAUAUCAU[dT][dT]
6A (SEQ ID NO: 536) 5 (SEQ ID NO: 910) 05L31 UAUAAUGAUAUUUUCAUAGAA[dT][dT] 05L317 UUCUAUGAAAAUAUCAUUAUA[dT][dT]
7A (SEQ ID NO: 537) 5 (SEQ ID NO: 911) 05L31 UGAUUAUAAUGAUAUUUUCAU[dT][dT] 05L318 AUGAAAAUAUCAUUAUAAUCA[dT][dT]
8A (SEQ ID NO: 538) 5 (SEQ ID NO: 912) 05L31 AUAAAUAGUGAUUAUAAUGAU[dT][dT] 05L319 AUCAUUAUAAUCACUAUUUAU[dT][dT]
9A (SEQ ID NO: 539) 5 (SEQ ID NO: 913) 05L32 AAAAGCUUAAUAAGAAUGGUU[dT][dT] 05L320 AACCAUUCUUAUUAAGCUUUU[dT][dT]
OA (SEQ ID NO: 540) 5 (SEQ ID NO: 914) 05L32 AAAAAGCUUAAUAAGAAUGGU[dT][dT] 05L321 ACCAUUCUUAUUAAGCUUUUU[dT][dT]
1A (SEQ ID NO: 541) 5 (SEQ ID NO: 915) 05L32 UAAAUGUACACAUUUAGCCAC[dT][dT] (SEQ 05L322 GUGGCUAAAUGUGUACAUUUA[dT][dT]
2A ID NO: 542) 5 (SEQ ID NO: 916) 05L32 AUAAAUGUACACAUUUAGCCA[dT][dT] 05L323 UGGCUAAAUGUGUACAUUUAU[dT][dT]
3A (SEQ ID NO: 543) 5 (SEQ ID NO: 917) 05L32 UAUAAAUGUACACAUUUAGCC[dT][dT] 05L324 GGCUAAAUGUGUACAUUUAUA[dT][dT]
4A (SEQ ID NO: 544) 5 (SEQ ID NO: 918) 05L32 UUCUAAUAUAAAUGUACACAU[dT][dT] 05L325 AUGUGUACAUUUAUAUUAGAA[dT][dT]
5A (SEQ ID NO: 545) 5 (SEQ ID NO: 919) 05L32 AAGAAUUAAAGAAAAGAUCUG[dT][dT] 05L326 CAGAUCUUUUCUUUAAUUCUU[dT][dT]
6A (SEQ ID NO: 546) 5 (SEQ ID NO: 920) 05L32 AAUAAGAAUUAAAGAAAAGAU[dT][dT] 05L327 AUCUUUUCUUUAAUUCUUAUU[dT][dT]
7A (SEQ ID NO: 547) 5 (SEQ ID NO: 921) 05L32 AAACCAAUAAGAAUUAAAGAA[dT][dT] (SEQ 05L328 UUCUUUAAUUCUUAUUGGUUU[dT][dT]
8A ID NO: 548) 5 (SEQ ID NO: 922) 05L32 ACUAUACCCACUAUUUAAGAG[dT][dT] (SEQ 05L329 CUCUUAAAUAGUGGGUAUAGU[dT][dT]
9A ID NO: 549) 5 (SEQ ID NO: 923) 05L33 ACAAAUGUGCAAUAUUAGCAC[dT][dT] 051330 GUGCUAAUAUUGCACAUUUGU[dT][dT]
OA (SEQ ID NO: 550) 5 (SEQ ID NO: 924) 05L33 AACAAAUGUGCAAUAUUAGCA[dT][dT] 05L331 UGCUAAUAUUGCACAUUUGUU[dT][dT]
1A (SEQ ID NO: 551) 5 (SEQ ID NO: 925) 05L33 AUGUUUCAUUCAUUCAUCCAU[dT][dT] 05L332 AUGGAUGAAUGAAUGAAACAU[dT][dT]
2A (SEQ ID NO: 552) 5 (SEQ ID NO: 926) 05L33 AGUAGUAUAUGUUUCAUUCAU[dT][dT] 05L333 AUGAAUGAAACAUAUACUACU[dT][dT]
3A (SEQ ID NO: 553) 5 (SEQ ID NO: 927) 05L33 AAUCAGUAGUAUAUGUUUCAU[dT] [dT] 05L334 AUGAAACAUAUACUACUGAUU[dT][dT]
4A (SEQ ID NO: 554) 5 (SEQ ID NO: 928) 05L33 AAAUAAUCAGUAGUAUAUGUU[dT] [dT] 05L335 AACAUAUACUACUGAUUAUUU[dT][dT]
5A (SEQ ID NO: 555) 5 (SEQ ID NO: 929) 05L33 AAUCAAAGUAAUUACAGUCAG[dT][dT] 05L336 CUGACUGUAAUUACUUUGAUU[dT][dT]
6A (SEQ ID NO: 556) 5 (SEQ ID NO: 930) 05L33 AUCUAAUCAAAGUAAUUACAG[dT][dT] 05L337 CUGUAAUUACUUUGAUUAGAU[dT][dT]
7A (SEQ ID NO: 557) 5 (SEQ ID NO: 931) 05L33 UUAUUUCCAGUUGUUUAUCUA[dT][dT] 05L338 UAGAUAAACAACUGGAAAUAA[dT][dT]
8A (SEQ ID NO: 558) 5 (SEQ ID NO: 932) 05L33 UUAUUAGAACUUUUUCAGCAG[dT][dT] 05L339 CUGCUGAAAAAGUUCUAAUAA[dT][dT]
9A (SEQ ID NO: 559) 5 (SEQ ID NO: 933) 05L34 UUUAUUAGAACUUUUUCAGCA[dT][dT] 051340 UGCUGAAAAAGUUCUAAUAAA[dT][dT]
OA (SEQ ID NO: 560) 5 (SEQ ID NO: 934) ID target start target sequence Location Size SEQ
position position ID
NO:

OSC4 63-85 63 CAGCATGAGCGGCGGTTGGATGG 5'UTR - 21 999 CDS

3'UTR

0SC46 995- 995 GGGCACACCAGCCCTCAGAGACC 3' UTR 21 0SC47 1006- 1006 CCCTCAGAGACCTGAGCTCTT 3' UTR 21 0SC48 1006- 1006 CCCTCAGAGACCTGAGCTCTTCT 3' UTR 21 0SC49 1008- 1008 CTCAGAGACCTGAGCTCTTCTGG 3' UTR 21 OSC50 1082- 1082 GGGTCCCTGGACACTCCCTATGG 3' UTR 21 OSC51 1085- 1085 TCCCTGGACACTCCCTATGGAGA 3' UTR 21 0SC52 1088- 1088 CTGGACACTCCCTATGGAGATCC 3' UTR 21 0SC53 1129- 1129 ACCTGCCACAGCCAGAACTGAGG 3' UTR 21 0SC54 1163- 1163 GGCAGCTCCCAGGGGGTAGAACG 3' UTR 21 0SC55 1176- 1176 GGGTAGAACGGCCCTGTGCTTAA 3' UTR 21 0SC56 1182- 1182 AACGGCCCTGTGCTTAAGACACT 3' UTR 21 0SC57 1184- 1184 CGGCCCTGTGCTTAAGACACTCC 3' UTR 21 0SC58 1237- 1237 TTGCTTCACATCCTCAAAAAAAA 3' UTR 21 0SC59 1238- 1238 TGCTTCACATCCTCAAAAAAAAA 3' UTR 21 ID Target Start Target sequence Location Size SEQ
ID
position position NO:

OS L272 14169- 14169 CTCTGAAGTATAGCTATACCAGC CDS/3'- 21 OS L273 14186- 14186 ACCAGCTATTTAGGGAATAATTA 3'-UTR 21 OS L274 14188- 14188 CAGCTATTTAGGGAATAATTAGA 3'-UTR 21 OS L275 14211- 14211 AACACACTTTTGCACATATATTT 3'-UTR 21 OS L276 14213- 14213 CACACTTTTGCACATATATTTTT 3'-UTR 21 OS L277 14236- 14236 TACAAACAGATGAAAAAAGTTAA 3'-UTR 21 OS L278 14252- 14252 AAGTTAACATTCAGTACTTTATG 3'-UTR 21 OS L279 14261- 14261 TTCAGTACTTTATGAAAAAAATA 3'-UTR 21 OS L280 14263- 14263 CAGTACTTTATGAAAAAAATATA 3'-UTR 21 OS L281 14341- 14341 CCGTCTCATATTTTTACAAATAA 3'-UTR 21 OS L282 14355- 14355 TACAAATAATTATCACAATGTAC 3'-UTR 21 OS L283 14366- 14366 ATCACAATGTACTATATGTATAT 3'-UTR 21 OS L284 14368- 14368 CACAATGTACTATATGTATATCT 3'-UTR 21 OS L285 14372- 14372 ATGTACTATATGTATATCTTTGC 3'-UTR 21 OS L286 14396- 14396 CTGAAGTTGTCTGAAGGTAATAC 3'-UTR 21 0SL287 14406- 14406 CTGAAGGTAATACTATAAATATA 3'-0SL288 14437- 14437 TTGTAAATTTTGGAAAGATTATC 3'-0SL289 14447- 14447 TGGAAAGATTATCCTGTTACTGA 3'-0SL290 14451- 14451 AAGATTATCCTGTTACTGAATTT 3'-0SL291 14457- 14457 ATCCTGTTACTGAATTTGCTAAT 3'-0SL292 14458- 14458 TCCTGTTACTGAATTTGCTAATA 3'-0SL293 14464- 14464 TACTGAATTTGCTAATAAAGATG 3'-0SL294 14503- 14503 GTGATCATTATAGTAAATGATCC 3'-0SL295 14513- 14513 TAGTAAATGATCCAACAAGAAAA 3'-0SL296 14523- 14523 TCCAACAAGAAAAGGAATTGACT 3'-0SL297 14579- 14579 CACTCATATTTCCTATAAAATTA 3'-0SL298 14581- 14581 CTCATATTTCCTATAAAATTATC 3'-0SL299 14633- 14633 GTCCATTTTTACACATTAGCACT 3'-OSL300 14649- 14649 TAGCACTTAATTAATGTTCAATA 3'-OSL301 14650- 14650 AGCACTTAATTAATGTTCAATAT 3'-0SL302 14652- 14652 CACTTAATTAATGTTCAATATTA 3'-0SL303 14665- 14665 TTCAATATTACATGTCAATTTGA 3'-0SL304 14684- 14684 TTGATTAATGGCTATGTTGATAG 3'-0SL305 14708- 14708 GGCCACTATGTGTTGTATAGACA 3'-0SL306 14711- 14711 CACTATGTGTTGTATAGACATCT 3'-0SL307 14767- 14767 AGGTAGGAAAAGCAATTCAGTTT 3'-0SL308 14856- 14856 GCCAAGACAACATTTTTATTTGT 3'-OS L309 14861- 14861 GACAACATTTTTATTTGTGATGT 3'-UTR 21 OS L310 14886- 14886 ATGAGGAAATCCCATATCATTAA 3'-UTR 21 OS L311 14921- 14921 TGCATTGAGTTTGTGGTTAATTA 3'-UTR 21 OS L312 14925- 14925 TTGAGTTTGTGGTTAATTAAATG 3'-UTR 21 OS L313 15034- 15034 AGCTGAATTTCTGAAACCAAATC 3'-UTR 21 OS L314 15049- 15049 ACCAAATCTGTGTCTTCATAAAA 3'-UTR 21 OS L315 15115- 15115 TGGGTTTTTGTTTCTATGAAAAT 3'-UTR 21 OS L316 15122- 15122 TTGTTTCTATGAAAATATCATTA 3'-UTR 21 OS L317 15126- 15126 TTCTATGAAAATATCATTATAAT 3'-UTR 21 OS L318 15130- 15130 ATGAAAATATCATTATAATCACT 3'-UTR 21 OS L319 15138- 15138 ATCATTATAATCACTATTTATTT 3'-UTR 21 OS L320 15188- 15188 AACCATTCTTATTAAGCTTTTTA 3'-UTR 21 OS L321 15189- 15189 ACCATTCTTATTAAGCTTTTTAT 3'-UTR 21 OS L322 15220- 15220 GTGGCTAAATGTGTACATTTATA 3'-UTR 21 OS L323 15221- 15221 TGGCTAAATGTGTACATTTATAT 3'-UTR 21 OS L324 15222- 15222 GGCTAAATGTGTACATTTATATT 3'-UTR 21 OS L325 15228- 15228 ATGTGTACATTTATATTAGAATG 3'-UTR 21 OS L326 15263- 15263 CAGATCTTTTCTTTAATTCTTAT 3'-UTR 21 OS L327 15266- 15266 ATCTTTTCTTTAATTCTTATTGG 3'-UTR 21 OS L328 15271- 15271 TTCTTTAATTCTTATTGGTTTTT 3'-UTR 21 OS L329 15438- 15438 CTCTTAAATAGTGGGTATAGTCT 3'-UTR 21 OS L330 15524- 15524 GTGCTAATATTGCACATTTGTTA 3'-UTR 21 0SL331 15525- 15525 TGCTAATATTGCACATTTGTTAA 3'-0SL332 15575- 15575 ATGGATGAATGAATGAAACATAT 3'-0SL333 15583- 15583 ATGAATGAAACATATACTACTGA 3'-0SL334 15587- 15587 ATGAAACATATACTACTGATTAT 3'-0SL335 15591- 15591 AACATATACTACTGATTATTTTA 3'-0SL336 15655- 15655 CTGACTGTAATTACTTTGATTAG 3'-0SL337 15659- 15659 CTGTAATTACTTTGATTAGATAA 3'-0SL338 15675- 15675 TAGATAAACAACTGGAAATAATG 3'-0SL339 15698- 15698 CTGCTGAAAAAGTTCTAATAAAT 3'-0SL340 15699- 15699 TGCTGAAAAAGTTCTAATAAATG 3'-Table 11 Additional table of siRNA sequences SEQ OSID antisense sequence (5 to 3') OSID
sense sequence (3' to 5) SEQ ID
ID
NO:S
957 OSC17C-1 CAGUUGCGCAGUUUCUUGUC OSC17B-1 [dT][dT]GUCAACGCGUCA 973 AGUUC[dT][dT]
AAGAACAGUCAAG
958 OSC17C-2 CAGUUGCGCAGUUUCUUGU[nn OSC17B-2 [dT][dTrG*UCAACGCGUC 974 ClinnA]GUUC[dT][dT] AAAGAACAGUCAAG
959 OSC17C-3 CAGUUGCGCAGUUUCU[nnU][nn OSC17B-3 [dT][dTrG*UCAACGCGUC 975 G]UCAGUUC[dT][dT]
AAAGAACAG[mU]CAAG
960 OSC17C-4 CAGUUGCGCAGUUUCU[nnU][nn OSC17B-4 [dT][dTrG*UCAACGCGUC 976 G]U[nnC][nnA]GUUC[dT][dT]
AAAGAA[mC]AGUCAAG
OSC17B-5 [dT][dTrG*UCAACGCGUC 977 AAAGAA[nnC]AG[nnU]CAA
G
OSC17B-6 [dT][dT]*G*UCAA[nnC]GCG 978 UCAAAGAA[mC]AG[nnU]C
AAG
961 OSC47C-1 AAGAGCUCAGGUCUCUGAGG OSC47B-1 [dT][dT]UUCUCGAGUCCA 979 G[dT][dT] GAGACUCCC
962 OSC47C-2 AAGAGCUCAGGUCUC[nnU]GA OSC47B-2 [dT][dTrU*UCUCGAGUCC 980 GGG[dT][dT] AGAGACUCCC
963 OSC47C-3 AAGAGCUCAGGUCUC[nnU][nnG] OSC47B-3 [dT][dTrU*UCUCGAGUCC 981 AGGG[dT][dT] AGAGA[mC]UCCC
OSC47B-4 [dT][dTrU*UCUCGAGUCC 982 AGAG[nnA][nnC]UCCC
OSC47B-5 [dT][dTrU*UCUCGAG[nnU] 983 CCAGAG[nnA][mC]UCCC

964 OSL231C-1 UUUGAUAGCACCAAACCUAGA OSL231B-1 [dT][dT]AAACUAUCGUGG 984 GCCC[dT][dT] UUUGGAUCUCGGG
965 OSL231C-2 UUUGA[nnU]AG[nnC]ACCAAACC[ OSL231B-2 [dT][dTrA*AACUAUCGUG 985 nnU]AGAGCCC[dT][dT] GUUUGGAUCUCGGG
966 OSL231C-3 UUUGAUAGCACCAAACC[nnU][ OSL231B-3 [dT][dT]*A*AACUA[nnU]CG[ 986 nnA]GAGCCC[dT][dT]
nnU]GGUUUGGA[nnU]CUC
GGG
967 OSL231C-4 UUUGAUAG[nnC]ACCAAACC[m OSL231B-4 [dT][dTrA*AACU[mA][mU] 987 U]AGAGCCC[dT][dT]
C[nnG][nnU]GGUUUGG[nnA]
[nnU]CUCGGG
968 OSL231C-5 UUUGAUAGCACCAAACC[nnU]A OSL231B-5 [dT][dTrA*AACUGUCGUG 988 GAGCCC[dT][dT]
GUUUGGA[nnU]CUCGGG
OSL231B-6 [dT][dTrA*AACUGUCG[nn 989 U]GGUUUGGA[nnU]CUCG
GG
OSL231B-7 [dT][dTrA*AACUAUCGUG 990 G[nnU]UUGGAUCUCGGG
969 0SL245C-1 UUUGCAAUGACUCUCCUAUCA 0SL245B-1 [dT][dT]AAACGUUACUGA 991 GUCC[dT][dT] GAGGAUAGUCAGG
970 0SL245C-2 UUUGCAA[nnU][nnG]ACUCUCC[ 0SL245B-2 [dT][dTrA*AACG[nnU]UA[nn 992 nnU][nnA]UCAGUCC[dT][dT]
C]UGAGAGGA[nnU]AGUC
AGG
971 0SL245C-3 UUUGCAAUGACUCUCC[nnU][nn 0SL245B-3 [dT][dTrA*AACGUUACUG 993 A]UCAGUCC[dT][dT]
AGAGGA[nnU]AGUCAGG
972 0SL245C-4 UUUGCAA[nnU][nnG]ACUCUCCU 0SL245B-4 [dT][dTrA*AACGUUA[nnC] 994 AUCAGUCC[dT][dT] UGAGAGGA[nn U]AG
UCAG
G
0SL245B-5 [dT][dTrA*AACGUUACUG 995 AGAGGAUAGUCAGG
Key to modifications [dT] = DNA base (T) within RNA oligo [mA], [mG], [mC], [mU] = 2'0-Methyl RNA
* = Phosphorothioate linkages

[00167] In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group including the sense sequences of any table herein and a second sequence that is selected from the group consisting of the corresponding antisense sequences of any table herein. A corresponding antisense sequence is a nucleotide sequence within the OSID family for example OSC17. In those instances when we refer to an siRNA
with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S or OSC17C-(n) paired with OSC17B-(n) where "n" is any number of the OSC17 family).

[00168] Unless otherwise specified, the compounds provided herein may be enantiomerically pure, such as a single enantionner or a single diastereonner, or be stereoisonneric mixtures, such as a mixture of enantionners, e.g., a racennic mixture of two enantionners; or a mixture of two or more diastereonners. Conventional techniques for the preparation/isolation of individual enantionners include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantionneric mixture, for example, chiral chromatography, recrystallization, resolution, diastereonneric salt formation, or derivatization into diastereonneric adducts followed by separation. It is understood that the phosphorothioate group, designated by an asterisk (*), constitutes a stereogenic center, and the presence of each such group in a sequence engenders two diastereoisonners. The number of such diastereoisonners in a double stranded RNAi agent may be calculated by the formula 2^n, wherein n represents the number of phosphorothioate groups in a sequence comprised of a double stranded siRNA.

[00169] In some embodiments, the antisense strand (identified with "A" in the OS ID name) and/or the sense strand (identified with "S" in the OS ID name) of an RNAi agent comprises or consists of a nucleobase sequence, for example, "OSC17A-1"
CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), and the nucleobase sequence may include at least one or more nucleotides as a modified nudeotide, and wherein SEQ ID NO: 17 is located at positions 1 to 25 (5'4 3') of the antisense strand and forms a duplex with the corresponding sense strand (identified as OSC17S-1. In some embodiments, the antisense strand of an RNAi agent comprises or consists of a nucleobase sequence for example CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), wherein all or substantially all or 1, 2, 3, 4 or 5 of the nucleotides are modified nucleotides (see for example SEQ ID NO. 24), and wherein SEQ ID NO: 24 is located at positions 1 to 27 (5 4 3') of the antisense strand. For any antisense or sense strand disclosed herein, in some embodiments, the antisense strand of an RNAi agent comprises or consists of the sequence (5 '4 3') wherein * is a phosphorothioate linkage between deoxy thynnine [dT]; and/or wherein nnC, nnA, mG, mU are 2'-0-methyl cytidine, 2'-0-methyl adenine, 2'-0-methyl guanosine, 2'-0-methyl uridine respectively; and/or wherein 2fA, 2fU, 2fG, 2fC
are 2'-fluoro adenine, 2'-fluoro uridine, 2'-fluoro guanosine, and 2'-fluoro cytosine respectively. The antisense target on the nnRNA is identified with the same name but without the notation of "A" or "S"
after the name. An antisense sequence with the same name, for example OSC17A-1 through OSC17A-18 binds to the same nucleotide target sequence.

[00170] Sequences shown in Table 4 were transfected into HEK
293 (human embryonic kidney) and MDA-MB-4355 (human melanoma) cell lines to determine their ability to reduce the protein expression of LRP2 and CD320 gene/protein. These two cell lines were chosen because of their relatively high expression levels of LRP2 as noted in the Human Protein Atlas at world wide web.proteinatlas.org and the NCI-60 gene expression profiles at discover.nci.nih.gov/cellminer/ so that a change in protein expression for LRP2 was easy to detect.

[00171] Referring now to FIG. 3A-B and FIG. 3D-E, HEK293 and MDA-MB-231 cells were transfected with 20nM of indicated siRNAs and incubated for 48 hours. Whole cell lysates were prepared and innnnunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs represent the fold change of protein levels compared to the scrambled siRNA control (OSS1).
(Average -1+ SEM is shown, n=3).

[00172] CD320 and LRP2 protein levels were determined by western blot and quantified by Image Studio Software (LiCor Company), relative to a control protein that is not affected by CD320 or LRP2 knockdown. To determine the efficacy of knockdown, protein levels of CD320 (FIG. 3 A-B) and LRP2 (FIG. 3 D-E) on the samples that were exposed to siRNA sequences against the nnRNA of either gene, were compared to that in the untreated and scrambled controls (black and gray bars, respectively, in all graphs of FIG. 3). We found that both siRNA sequences directed against CD320 (05C17 and 05C47) almost completely abrogated CD320 expression (circles in FIG. 3 A-B). siLRP2 sequences resulted in variable efficiency in reducing LRP2 protein. Two sequences (05L231 and 05L245) consistently reduced LRP2 levels 75% or more in both cell lines (circles FIG 3 B, E).

[00173] Referring now to FIG. 6, lysates were made from transformed (HEK293) and representative cancer cell lines, and western blot was performed to determine LRP2 protein levels.
The cancer cells screened have low levels of LRP2 expression. The results represent the averages +SEM of three independent lysates. The data suggests that the cancer cells screened have very low levels of LRP2 expression.

[00174] We transfected a panel of LRP2 and CD320 siRNAs into cancer cell lines derived from multiple tissues and analyzed the levels of LRP2 protein and CD320 protein in the cell line.
Representative cell lines from prostate, breast and glioblastonna, and normal fibroblasts were exposed to CD320 and LRP2 siRNAs in an experimental set-up similar to that described for HEK293 and MDA-MB-4355 cells. The results are shown in Fig 3 C, F, and FIG. 4.

[00175] Referring now to FIG. 3 C, F; and FIG. 4, MDA-MB-231 LnCAP, MCF-7 and U251 cells were exposed to siRNA sequences to knockdown CD320 (FIG. 3C, and FIG. 4 A-C) and LRP2 (FIG. 3 F, and FIG. 4 D-F), in a similar fashion as described for the data represented in FIG. 3 A, B, D, and E. CD320 protein knockdown FIG. 3C, and FIG. 4 A-C, compared to the untreated or scrambled controls, is more than 90% for all cell lines tested. LRP2 knockdown is accomplished in all cell lines too. However, the level of knockdown is less in the LnCAP cells compared to the other cell lines and the sequences that are effective may differ as well (FIG. 3 F, and FIG. 4 D-F).

[00176] Referring now to FIG. 5, an experimental set up similar to that described in FIG. 3 was employed. Additional prostate and brain cancer cell lines, as well as normal fibroblast, were exposed to siRNAs directed against CD320. Levels of CD320 were nearly abrogated in DU-145 (prostate) cells, whereas the levels of knockdown in A172 brain cells and normal fibroblasts were 21%-33% and 25%-28%, respectively (FIG. 5 A-C).

[00177] From these studies we can conclude that two siRNAs to CD320 (OSC17 and 0SC47) are very effective in knocking down CD320 protein levels (80% or more), in nearly every cell line tested. While LRP2 is theoretically harder to knock down because of its size, we have identified two siRNAs, 0SL231 and 0SL245, that consistently knock down LRP2 in most cell lines in which we can detect LRP2.

[00178] In addition, LRP2 protein expression levels are very high in HEK 293 cells and easily detectable by western blot. Cancer cell lines have much lower expression of LRP2 compared to HEK293 cells as measured by western blot (FIG. 6), and some cell lines may contain LRP2 at levels below reliable detection.

[00179] Referring now to FIG. 7, the effects of doxorubicin treatment on cell viability, as measured by the CTG assay, are illustrated. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate. The next day, cells were treated with doxorubicin at the indicated concentrations.
Four days after the doxorubicin exposure was initiated, the cells were assayed for viability using the CTG assay. The line indicates the non-linear fitting of the data to calculate an IC50 value. Instead of visually assessing the effect of CD320/LRP2 gene expression knockdown on cell proliferation (as shown for shRNA-mediated CD320/LRP2 knockdown in FIG. 2), a functional assay for quantitating the effect on cell viability of the simultaneous knockdown of LRP2 and CD320 by siRNA was developed. A widely used assay for the measurement of cell viability is the Pronnega Cell-titer GLO
platform (CTG), which quantifies ATP levels in the cell (live cells produce ATP, dead cells do not).
After incubating the cells with the CTG reagent, ATP levels can be indirectly measured as light production using the TECAN luminescence plate reader. As a first step, toxicity of a known chemotherapeutic drug, doxorubicin, was assayed on the cell lines of interest.
Doxorubicin was used as a positive control for cell toxicity in our assay. Representative data from A172 brain cancer cells (FIG. 7A) and HCC15 lung cancer cells (FIG. 7B) exposed to doxorubicin are shown in FIG. 7. From this data, the IC50 of doxorubicin treatment on these cell lines was determined: 132 nm for A172 cells and 167 nnn for HCC15 cells. Based upon these findings, a larger screen was initiated to determine the IC50 of doxorubicin in several cancer and non-cancer cell lines, to determine the doxorubicin dose to use when cell lines are used in the viability assay to test the simultaneous knockdown of CD320 and LRP2. The results of the cell lines tested are summarized in Table 8 IC50 determination of doxorubicin.

[00180] To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay. A schematic of this experimental setup is presented in FIG. 8.

Table 8 Cancer type Cell line IC50 (nM) Glioblastoma A172 132 Breast MDA-MB-231 43 Prostate DU145 248 Lung NCI-H460 56 Melanoma MDA-MB-435S 325 Other GM05659 267

[00181] The cells lines were plated at 1,000 to 4,000 cells/well in a 96-well plate and treated with doxorubicin the following day. CTG activity was measured 4 days after treatment. IC50 values were calculated by GraphPad Prism Software. Results are tabulated in Table 8.

[00182] These data show that doxorubicin works efficiently on this CTG platform (i.e., doxorubicin kills cancer cells) and can thus be used as a positive control in the in vitro assay to compare the cytotoxic effects of siRNA-knockdown of CD320 and LRP2. In this latter assay, normal or cancer cells are transfected with individual or combinations of siRNAs sequences that are targeting CD320 or LRP2 specifically or control siRNAs, similar to the experiments that provided the data for FIG, 3, 4, and 5. In FIG. 3, 4, and 5, protein levels are measured, but in the in vitro assay, cell viability is measured.

[00183] Referring now to FIG. 8, an overview of a functional assay for screening (ds) siRNA
effects on cell proliferation is illustrated. To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines were analyzed for cell growth by the CTG assay.

[00184] Now, referring to FIG. 10B, MDA-MB-231 triple negative breast cancer cells were plated in a 24-well plate at 20,000 cells/well. Cells were transfected the next day with an siRNA
selected from the group of OSC17, 0SC47, 0SL231, and 0SL245 at 20nM. Cells were also transfected with combinations of two siRNAs each of 10nM, one of these targeting CD320 and the other LRP2, with the siRNAs targeting CD320 selected from the group of OSC17 and 0SC47, and the LRP2 targeting siRNAs selected from the group of 0SL231 and 0SL245, each dosed at 10nM. Cells were repeated transfected 4 times over the course of 11 days as indicated in Table 9. At day 11, cells were analyzed for cell growth by the CTG assay. The percent cell survival compared to the non-targeting control (OSS2) is shown. The data represented is the average of 6 experiments -/+ SEM.

[00185] Now, referring to FIG. 11, MDA-MB-231 and DU-145 cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA
targeting LRP2 (05L245). Cells were also transfected with a combination of a CD320 targeting siRNA (OSC17) and LRP2 targeting siRNA (05L24), over a range of concentrations (2-20 nM), so the concentration of the two siRNAs equaled 20 nM total siRNA transfected, as indicated in FIG. 11.
Cells were repeatedly transfected as indicated in Table 9, and the percent cell survival is shown.

[00186] Now, referring to FIG. 12, MDA-MB-231 breast cancer cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA
targeting LRP2 (05L245). Each day, over five days, lysates were prepared.
Western blotting was performed on the lysates for CD320 protein levels (FIG.12A) or LRP2 protein levels (FIG. 12B).

[00187] Referring now to FIG. 9 and FIG. 10, data quantifying the effects of knocking down CD320 and LRP2 in various cell lines is represented. Cell lines representative of several types of cancers or normal fibroblasts were transfected with individual or combinations of siRNAs to CD320 or LRP2 as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin treated cells served as a positive control for cell toxicity in our assays.

[00188] The data of the individual experiments presented in FIG. 9 and FIG. 10 and additional cell lines we have screened are summarized in Table 9. These experiments show the broad applicability of siCD320 and siLRP2 toxicity in a variety of cancer types.

[00189] Referring now to FIG. 13, a schematic of PEI and siRNA complexes is illustrated.
PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) form of the PEI-siRNA complex, which are able to enter the cell via an endocytotic or pinocytotic mechanism.

[00190] Referring now to FIG. 14, siRNAs are short RNA
duplexes of generally 16 to 30 nucleotides; the sequence of the siRNA is complementary to a nnRNA expressed in the cell.

Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA
duplexes are unwound via the RISC (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary nnRNA molecule. The nnRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity. The end result is that the nnRNA targeted by the siRNA is degraded, and the protein encoded by the nnRNA is not produced. This causes the "knockdown" effect or reduced protein levels of the gene targeted by the siRNA
compared to control-treated cells.

[00191] Referring now to FIG. 15 effectiveness of INTERFERin in delivering siRNAs to cancer cells is illustrated. 2 nM of indicated siRNAs were transfected into A172 and MDA-MB-4355 cells as per the manufacturers protocol. Cell lysates were prepared 3 days post-infection and analyzed by western blot for CD320 protein levels. OSS1 and OSS2 are non-targeting siRNA
controls. In this experiment, both sequences were tested. CD320 protein levels were knocked down to 9% to 18% for A172 cells and 26% to 48% for MDA-MB-4355 cells, compared to OSS1. Much more efficient knockdown of CD320 is observed when the siRNAs were delivered with other transfection reagents (e.g. RNAiMAX, Viromer Blue) that were used in the experiments described previously particularly for MDA-MB-4355 cells. The Polyplus INTERFERin platform has been tested in vitro in our laboratory in a proof of principle experiment, whereby the platform is able to deliver siRNAs to the target cells in vitro.

[00192] Referring now to FIG. 16, treatment of breast, prostate, and skin cancer cells with an inhibitor of CD320 receptor or an inhibitor of LRP2 receptor or a combination of both in an amount effective to inhibit proliferation of the cancer cells as compared to the control cells treated with control siRNA is illustrated. MDA-MB-231, DU145, LnCAP, and MDA-MB-4355 cells were plated at 20,000 cells per well in a 24-well plate. The next day, the cells were transected with 20 nM of indicated siRNAs to knock down CD320, LRP2, or scrambled control. For the combination of siRNAs, cells were treated with 10 nM of each siRNA for 20 nM total treatments. Cells were repeatedly transfected as in Table 9 for the length of time indicated in Table 9. The indicated pictures of the cells were taken at the end of the experiment.

[00193] Table 9. Summary of functional siRNA data screening n Single siRNA knockdown Double siRNA
knockdown DOX
Cell line # of Days (siCD320) (siLRP2) 05C17 +
05C47 +
txns expt OSC- OSC- OSL- OSL- OSL OSL OSL OSL

Normal Lung Melanoma Prostate LnCAP 3 4 7 52 42 72 60 68 51 52 57 38 Glioblastoma Breast Note: The numbers represent percent survival compared to negative control OSS2.

[00194] A murine human tumor xenograft model was established using triple-negative breast cancer cells (MDA-MB-231) injected into the flanks of nude mice to test the efficacy of combined dosing of OSC17 and 0SL245. The administration of the drug is by repeated dosing over a range of drug concentrations using intratunnoral, iv, ip or specialized route of administration. The dosing schedule is based on pilot studies to determine the tolerability of the delivery vehicle and the drug and will incorporate ranges that are taught in the art. Among the delivery platforms are nanoparticles, liposonnes, micelles, polymers, small molecule conjugates, aptanners and antibody conjugates. Hybrid technologies containing elements of the aforementioned delivery systems are also known.

[00195] The manufacturing process consists of synthesizing the two single strand oligonucleotides of the duplex by conventional solid phase oligonudeotide synthesis. After purification, the two oligonucleotides are annealed into the duplex.

[00196] In vivo JetPEI is a cationic polymer delivery system that binds the negatively charged siRNA molecules to the cationic polyannine polymer. Its use has been reported in xenograft models using MCF-7 (breast), MDA-MB-231 (breast) and A549 (lung) cell lines both ip and intratunnoral. This delivery system is currently used in seven human clinical trials (Table 10). The formulated siRNAs are reported to be very stable.
Table 10 ¨ Clinical trial use of in vivo-jetPEI
Organization Type of study Phase Cancer Targeting Imaging and cancer Pre-clinical Systems therapy Benitec Lung metastases Pre-clinical Avena Blood-brain barrier Pre-clinical BiOncoTech Melanoma Phase 1 immunotherapy Ottawa Hospital Research Acute myocardial Phase 1 Institute infarction gene therapy CHU-Toulouse, Rangueil Pancreatic cancer gene Phase 2 Hospital therapy BioCancell Bladder cancer gene Phase 3 therapy

[00197] Note that in the specification and claims, "about" or "approximately" means within twenty percent (20%) of the numerical amount cited. Although the invention has been described in detail with particular reference to these embodiments, other embodiments can achieve the same results. For example, antisense oligonucleotides that are complimentary to the target nnRNA can inhibit expression of the protein of interest even though the antisense oligonucleotide is not provided as a dsRNA and may not bind to RISC/AGO complex. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above are hereby incorporated by reference.

Claims (68)

WHAT IS CLAIMED IS:

1. A double stranded RNA interference (RNAi) agent comprising:
(i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, (h) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA.

2. The double stranded RNAi agent of claim 1 wherein the antisense strand of (i) the first dsRNA
includes a region of complementarity to a CD320 RNA transcript.

3. The double stranded RNAi agent of claim 1 wherein the sense strand of (i) the first dsRNA is selected from Table 5 CD320.

4. The double stranded RNAi agent of claim 1 wherein (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 16-30 nucleotide pairs in length.

5. The double stranded RNAi agent of claim 1 wherein (i)the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 21-23 nucleotide pairs in length.

6. The double stranded RNAi agent of claim 1 wherein at least one strand of: (0 the first dsRNA
or 00 the second dsRNA comprises a 3' overhang of at least 2 nucleotides.

7. The double stranded RNAi agent of claim 1 wherein the antisense strand of (0 the first dsRNA, comprises the nucleotide sequence selected from (5' 4 3') AUCCAACCGCCGCUCAUGCUG[dT][dT] (SEQ ID NO: 4);
ACUGGAACUUGGUGGGUGGGC[dT][dT] (SEQ ID NO: 8);
UCCUCAUCGCUGCCAUCGCUG[dT]PT] (SEQ ID NO: 12);
AGUUUCUUGUCAGUUCCCCCA[dT][dT] (SEQ ID NO: 16);
UUCCAGACUGGUCUCCGGCAG[dI][dT] (SEQ ID NO: 48);
ACAAAAGGAGGAGGGUGGCGG[dT][dT] (SEQ ID NO: 52);
UCUGUUCUGACAGCAGCAGGG[dT][dTI(SEQ ID NO: 57);
UCUCUGAGGGCUGGUGUGCCC[dT]RIT] (SEQ ID NO: 63);
AGUGUCUUAAGCACAGGGCCG[dTildT] (SEQ ID NO: 91);
UUUUUUUGAGGAUGUGAAGCA[dTI[dT] (SEQ ID NO: 93); and the sense strand is at least substantially complementary to the antisense strand.

8. The double stranded RNAi agent of claim 1 wherein the antisense strand of (i) the first dsRNA, comprises the nucleotide sequence selected from (5' 4 3') AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64);
AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65);
mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmGdT*dT (SEQ ID NO 66);
mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmG (SEQ ID NO 68);
mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmGd-rdT (SEQ ID NO 71);
mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmG (SEQ ID NO 72);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO 75);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 76);
mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 77);
mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO 78);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdrdT (SEQ ID NO 79);
2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fC2fU2fG2fA2fG2fG2fG (SEQ ID NO 81);
wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and " is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

9. The double stranded RNAi agent of claim 1 wherein the sense strand of (i) the first dsRNA is no more than 30 nucleotides in length, and the antisense strand of (i) the first dsRNA is no more than 30 nucleotides in length.

10. The double stranded RNAi agent of claim 1 wherein the antisense strand of (ii) the second dsRNA includes a region of complementarity to an LRP2 RNA transcript.

11. The double stranded RNAi agent of claim 1 wherein the antisense strand and the sense strand of (ii) the second dsRNA are selected from Table 6 LRP2.

12. The double stranded RNAi agent of claim 1, wherein the antisense strand of (ii) the second dsRNA comprises the nucleotide sequence selected from (5' 4 3') AAUAAAUAACCAACAGUUGGG[dT][dTHSEQ ID NO: 213);
UUUAAAUACUGAACUACUGUG[dT][dTRSEQ ID NO: 230);
AAUCUAUUGCAAUAGUUUCAG[dT][dTHSEQ ID NO: 268);
AUUGAAACAACAAUGAAAGAG[dT][dT](SEQ.ID NO:309);
UUUUCAAAUUCCUAUCUACCC[dTOTRSEQ ID NO: 327);
AAUCCAAUACAAUCUCUUCUCVITWITHSEQ ID NO: 383);

ACACAAUGUCCACUUGUACACKMTHSEQ ID NO: 395);
UAUUCUGUACAAGGUUUAGGGVITildThSEQ ID NO: 403);
AUUUUAUAGGAAAUAUGAGUG[dT][dT1(SEQ ID NO: 517);
UAUAAAUGUACACAUUUAGCCNTI[dT](SEQ ID NO: 544); and the sense strand is at least substantially complementary to the antisense strand.

13. The double stranded RNAi agent of claim 1, wherein the antisense strand of (ii) the second dsRNA comprises the nucleotide sequence selected from (5' 4 3') UUUGCAAUGACUCUCCUAUCAGUCCdTdT(SEQ ID NO: 448);
UUUGCAAUGACUCUCCUAUCAGUCCdT*dT (SEQ ID NO: 449);
mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmCdrdT (SEQ
ID NO: 450);
mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmC (SEQ ID NO:
452);
mU21UmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdrdT (SEQ
ID NO: 455);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmC (SEQ ID NO:
456);
mU21UmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fCmU2fC
mC (SEQ ID NO: 458);
2fUmU2fUmG2fCmA2fAmU2fGmA2fCmU2fCmU2fCmC2fUmA2fUmC2fAmG2fUmC2fCdT*dT (SEQ
ID NO: 459);
mU2fAmU2fCmC2fUmA2fAmG2fUmC2fAmC2fAmC2fGmU2fUmU2fGmA2fCmU2fGmC (SEQ ID NO:
460);
mU2fU2fU2fG2fC2fA2fA2fU2fG2fA2fC2fU2fC2fU2fC2fC2fU2fA2fU2fC2fA2fG2fU2fC2fCdrdT
(SEQ
ID NO: 461);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdrdT (SEQ
ID NO: 463);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU (SEQ ID NO: 464);
mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fC2fU2fA2fU2fC2fA2fG2fU (SEQ ID NO: 465) wherein, mA, mC, mG, and mU are 2'-0-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and " is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

14. The double stranded RNAi agent of claim 1, wherein the sense strand of (ii) the second dsRNA is no more than 30 nucleotides in length, and the antisense strand is no more than 30 nucleotides in length.

15. The double stranded RNAi agent of claim 1 comprises (iii) the combination of (i) the first dsRNA and (ii) the second dsRNA.

16. The double stranded RNAi agent of claim 15 wherein the antisense strand of (i) the first dsRNA is selected from CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17);
CAGUUGCGCAGUUUCUUGUCAGUUCdrdT (SEQ ID NO 18);
AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64); and AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65); and the antisense strand of (ii) the second dsRNA is selected from UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417);
UUUGAUAGCACCAAACCUAGAGCCCdT*dT (SEQ ID NO: 418);
UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 448); and UUUGCAAUGACUCUCCUAUCAGUCCdT*dT (SEQ ID NO: 449);
wherein * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

17. The double stranded RNAi agent of claim 1 wherein (i) the first dsRNA
has the duplex structure of (SEQ ID NOs: 4 and 97) or (SEQ ID NOs: 8 and 101).

18. The double stranded RNAi agent of claim 1 wherein (h) the second dsRNA
has the duplex structure of (SEQ ID NOs: 213 and 587) or (SEQ ID NOs: 230 and 604).

19. An isolated cell comprising a double stranded RNAi agent of claim 1.

20. A pharmaceutical composition for inhibiting expression of a CD320 gene, the pharmaceutical composition comprising a double stranded RNAi agent (i) and (11) of claim 1.

21. A pharmaceutical composition for inhibiting expression of an LRP2 gene, the composition comprising a double stranded RNAi agent (i) and (ii) of claim 1.

22. The pharmaceutical composition of claim 20 further comprising an excipient

23. The pharmaceutical composition of claim 21 further comprising an excipient

24. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of CD320 in an amount effective to inhibit proliferation of the CC.

25. The method of claim 24 wherein the CC expresses CD320.

26. The method of claim 24 wherein the CC is from a cancer selected from melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

27. The method of claim 24 wherein the inhibitor is selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and an RNAi agent that hybridizes to a nucleic acid encoding CD320.

28. A method for treating a therapeutically-resistant cancer in a subject who has previously received a therapy, comprising administering to the subject an inhibitor of CD320 in an amount effective to inhibit or kill cancer cells (CCs) present in the therapeutically-resistant cancer.

29. The method of claim 28 wherein the CCs express CD320.

30. The method of claim 28 wherein the CC is from a cancer selected from melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

31. The method of claim 28 wherein the inhibitor is selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic add sequence encoding CD320.

32. A method for treating cancer in a subject who has recurring or relapsed cancer comprising administering to a subject an inhibitor of CD320 in an amount effective to inhibit or kill CCs in the cancer.

33. The method of claim 32 wherein the CCs express CD320.

34. The method of claim 32 wherein the CC is from a cancer selected from melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

35. The method of claim 32 wherein the inhibitor is selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid sequence encoding CD320.

36. The method of any one of claims 27, 31 and 35 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class, or a small molecule or protein inhibitor of C0320 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA encoding for CD320.

37. The method of any one of claims 27, 31 and 35 wherein the method further comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA
encoding for CD320.

38. The method of any one of claims 27, 31 and 35 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class (e.g., HDAC inhibitors), or the small molecule or protein inhibitor of C0320 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA
encoding for CD320.

39. The method of any one of claims 27, 31 and 35 wherein the method further comprises administering metformin in combination with an RNAi agent that hybridizes to an mRNA encoding for CD320.

40. The method of any one of claims 27, 31 and 35 wherein the RNAi agent comprises an antisense strand of Table 5.

41. The method of any one of claims 27, 31 and 35 wherein the method further comprises administering an RNAi agent that hybridizes to an mRNA encoding for LRP2 in combination with the RNAi agent that hybridizes to a nucleic acid sequence encoding CD320.

42. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of LRP2 in an amount effective in inhibiting proliferation of the CC.

43. The method of claim 42 wherein the CC expresses LRP2.

44. The method of claim 42 wherein the CC is from a cancer selected from the group consisting of melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

45. The method of claim 42 wherein the inhibitor is selected from the group consisting of an antibody that binds LRP2, a small molecule inhibitor of LRP2, and an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2.

46. A method for treating a therapeutically-resistant cancer in a subject who has previously received a therapy, comprising administering to the subject an inhibitor of LRP2 in an amount effective to inhibit or kill cancer cells (CCs) present in the therapeutically-resistant cancer.

47. The method of claim 46 wherein the CCs express LRP2.

48. The method of claim 46 wherein the CC is from a cancer selected from the group consisting of melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

49. The method of claim 46 wherein the inhibitor is selected from the group consisting of an antibody that binds LRP2, a small molecule inhibitor of LRP2, and a RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2.

50. A method for treating cancer in a subject who has recurring or relapsed cancer comprising administering to a subject an inhibitor of LRP2 in an amount effective to inhibit or kill CCs in the cancer.

51. The method of claim 50 wherein the CCs express LRP2.

52. The method of claim 50 wherein the CC is from a cancer selected from the group consisting of melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

53. The method of any one of claim 42, 46, and 50 wherein the inhibitor is selected from the group consisting of an antibody that binds LRP2, a small molecule inhibitor of LRP2, and an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2.

54. The method of any one of claims 42, 46, and 50 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class, or the small molecule or protein inhibitor of LRP2 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

55. The method of any one of claims 42, 46, and 50, wherein the method further comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA
encoding for LRP2.

56. The method of any one of claims 42, 46, and 50 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class (e.g., HDAC inhibitors), or a small molecule or protein inhibitor of LRP2 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

57. The method of any one of claims 42, 46, and 50 wherein the method further comprises administering metformin in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

58. The method of any one of claims 42, 46, and 50 wherein the RNAi agent comprises an antisense strand and a sense strand from Table 6.

59. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective to inhibit proliferation of the CC.

60. The method of claim 59 wherein the CCs express CD320 and LRP2.

61. The method of claim 59 wherein the CC is from a cancer selected from the group consisting of melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, renal carcinoma, hepatocellular carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

62. The method of claim 59 wherein the composition is a cocktail comprising i) the CD320 inhibitor selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid encoding CD320 and any combination thereof, and ii) the LRP2 inhibitor selected from an antibody that binds LRP2, a small molecule inhibitor of LRP2, and a RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2 and any combination thereof.

63. The method of any one of claims 62 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class.

64. The method of claim 62 wherein the RNAi agent that hybridizes to the mRNA encoding for CD320 comprises a first double-stranded ribonucleic acid (dsRNA) for inhibiting expression of CD320, wherein the first dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a CD320 RNA transcript and the RNAi agent that hybridizes to the mRNA encoding for LRP2 comprises a second dsRNA for inhibiting expression of LRP2, wherein the second dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an LRP2 RNA transcript.

65. The method of claim 64 wherein the antisense strand that is complementary to CD320 RNA
transcript is selected from Table 5 and the antisense strand that is complementary to the RNA
transcript for LRP2 is selected from Table 6.

66. The method of claim 62 wherein the method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class.

67. The method of claim 62 wherein the method further comprises administering a cancer therapeutic selected from the immunomodulatory class.

68. The method of claim 62 wherein the method further comprises administering metformin.