WO2024102114A1 - Methods and compositions for treating wolfram syndrome - Google Patents
Methods and compositions for treating wolfram syndrome Download PDFInfo
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- WO2024102114A1 WO2024102114A1 PCT/US2022/049125 US2022049125W WO2024102114A1 WO 2024102114 A1 WO2024102114 A1 WO 2024102114A1 US 2022049125 W US2022049125 W US 2022049125W WO 2024102114 A1 WO2024102114 A1 WO 2024102114A1
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Definitions
- BACKGROUND Wolfram syndrome is a genetic disorder characterized by juvenile onset diabetes, progressive blindness, and neurodegeneration. There is currently no treatment to delay, halt, or reverse the progression of this disease. Accordingly, treatment methods for patients with Wolfram syndrome are needed.
- the diabetes is insulin-dependent diabetes. In some embodiments, the diabetes is juvenile onset diabetes. In some embodiments, the subject has or is at risk for developing optic nerve atrophy. In some embodiments, the subject has or is at risk for developing a hearing impairment. In some embodiments, the subject has one or more mutations in the Wolframin (WFS1) gene. In some embodiments, the subject has the c.1672C>T, p.R558C mutation in the WFS1 gene. In some embodiments, the subject has the c.2654C>T, p.P885L mutation in the WFS1 gene. In some embodiments, the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene.
- WFS1 Wolframin
- the subject has the c.1672C>T, p.R558C mutation in the WFS1 gene.
- the subject has the c.2654C>T, p.P885L mutation in the WFS1 gene.
- the subject has one or more
- the TURSO and the sodium phenylbutyrate are administered once a day or twice a day. In some embodiments, TURSO is administered to the subject at a dose of about 5mg/kg to about 100 mg/kg. In some embodiments, sodium phenylbutyrate is administered to the subject at a dose of about 10mg/kg to about 400 mg/kg. In some embodiments, the TURSO is administered at an amount of about 0.5 to about 5 grams per day. In some embodiments, the sodium phenylbutyrate is administered at an amount of about 0.5 grams to about 10 grams per day.
- the methods include administering to the subject 1 gram of TURSO and 3 grams of sodium phenylbutyrate once a day or twice a day. In some embodiments, the methods include administering to the subject 1 gram of TURSO once a day and 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering to the subject about 1 gram of TURSO twice a day and 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the TURSO and the sodium phenylbutyrate are administered orally. In some embodiments, the TURSO and the sodium phenylbutyrate are formulated as a single powder formulation.
- the methods further include administering one or more additional therapeutic agents to the subject.
- the one or more additional therapeutic agents is valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, or ER Ca2+ stabilizers.
- GLP glucagon-like peptide
- dantrolene sodium or ER Ca2+ stabilizers.
- FIGS. 1A-1B Carrier frequencies and clinical manifestation of WFS1 c.1672C>T, p.R558C variant.
- FIGS. 1A Carrier frequencies for WFS1 c.1672C>T, p.R558C in subjects of Ashkenazi, Ashkenazi/Sephardi and Sephardi descent.
- FIG. 1B Carrier frequencies for WFS1 c.1672C>T, p.R558C by country origin.
- FIG. 1A Carrier frequencies for WFS1 c.1672C>T, p.R558C by country origin.
- FIGS. 3A-3H WFS1 p.R558C is more stable in the cell compared to p.P885L variant
- FIG. 3A Diagram of WFS1 protein showing the location of two variants, R558C and P885L.
- FIG. 3B Thermal profiles of WFS1 variants (WT, R558C and P885L) measured using SplitLuc tagged reporters expressed in HEK293T cells (Data from 3 independent experiments).
- FIG. 3D Fold change of luminescence intensities of WFS1 variants treated with proteasome inhibitor, bortezomib, for 24 hours (**P ⁇ 0.01 and ***P ⁇ 0.001 by unpaired t-test compared to untreated).
- FIG. 3E (Left) Representative blotting image of WFS1 (HA) and ⁇ -Tubulin in CHX chase assay. Lower panel of WFS1 (HA) is long-exposure image.
- FIG. 4A A schematic of Wolfram syndrome etiology and the targets to modulate by a combination treatment of 4-PBA and TUDCA (P+T).
- FIG. 4E Representative immunofluorescence images of neural progenitor cell (NPC) markers in NPCs differentiated from patient-derived iPSCs. Scale bar: 100 ⁇ m.
- FIG. 4G Mitochondrial respiration of NPCs treated with or without P+T for 48 hours represented as percentage of baseline oxygen consumption rate (OCR) measurements.
- OCR oxygen consumption rate
- FIGS. 5A-5C Comparison of ER stress levels in NPCs among cell lines.
- FIG. 5A Representative immunofluorescence image of neural progenitor cell (NPC) markers in NPCs differentiated from control iPSC line AN1.1. Scale bar: 100 ⁇ m.
- FIGS. 6A-6B Comparison of each treatment effect on WFS1 protein and ER stress levels.
- FIGS. 7A-7C Comparison of each treatment effect on mitochondrial DNA contents, mitochondrial membrane potentials and apoptosis.
- FIG. 7A Relative mitochondrial DNA (mtDNA) copy numbers normalized to nuclear DNA (nDNA) measured by qPCR analysis in NPCs treated with or without 4-PBA, TUDCA or P+T for 48 hours.
- mtDNA Relative mitochondrial DNA
- FIG. 7C (Upper) Representative blotting image of cleaved-Caspase3 and ⁇ -Tubulin in NPCs treated with or without 4-PBA, TUDCA or P+T for 48 hours.
- FIGS. 8A-8B P+T treatment reduced caspase 3/7 activity in NPCs derived from patients with typical Wolfram syndrome.
- FIG.8A Information on the four patients with typical Wolfram syndrome, including the genetic location of autosomal recessive pathogenic variants in WFS1 and the onset age of symptoms. The ages indicate when subjects were included in the study.
- FIGS. 9A-9I Insulin secretion is increased by a combination treatment of 4-PBA and TUDCA in SC-islets with WFS1 c.1672C>T, p.R558C variant.
- FIGS. 9A Representative flow cytometry dot plots and (FIG.
- FIG. 9F A schematic of P+T verification in SC-islets.
- FIG. 9G (Upper) Representative blotting images of WFS1 and ⁇ -Tubulin in stage 6 SC-islets treated with or without P+T for 7 days.
- (Lower) A quantification of WFS1 protein levels normalized with ⁇ - Tubulin. (n 3, *P ⁇ 0.05 by unpaired t-test compared to Ctrl).
- CP C-peptide
- CHGA Chromogranin A.
- FIGS. 11A-11B in vivo verification of a combination treatment with chemical chaperones (FIG. 11A) IP-GTT with WT or Wfs1 KO mice at baseline and 1 month after feeding with either Ctrl or P+T chow. (FIG. 11A)
- FIGS. 12A-12G Additional in vivo verification of a combination treatment with chemical chaperones. (FIG.
- FIG. 12B Food consumption rate in Wfs1 KO mice fed with either Ctrl or P+T chow.
- Taurursodiol (TURSO)) and a phenylbutyrate compound can be used for treating one or more symptoms of Wolfram syndrome.
- the present disclosure provides methods of treating at least one symptom of Wolfram syndrome in a subject by administering a bile acid (e.g. TURSO) and a phenylbutyrate compound (e.g. sodium phenylbutyrate).
- a bile acid e.g. TURSO
- a phenylbutyrate compound e.g. sodium phenylbutyrate
- the subjects in need of treatment can have or be at risk for developing diabetes, optic nerve atrophy, or a hearing impairment.
- Wolfram syndrome is a rare genetic disorder that can be caused by pathogenic variants in the Wolframin (WFS1) gene or, in a small fraction of patients, pathogenic variants in the CDGSH iron sulfur domain protein 2 (CISD2) gene; and manifested by diabetes insipidus, diabetes mellitus (e.g. juvenile-onset insulin-dependent diabetes), optic nerve atrophy, and progressive neurodegeneration. Many patients also develop other symptoms, ranging from hearing loss and endocrine deficiencies to neurological and psychiatric conditions.
- WFS1 pathogenic variants in the Wolframin
- CISD2 iron sulfur domain protein 2
- Wolfram syndrome is best characterized as a spectrum disorder.
- Wolfram syndrome is a progressive neurodegenerative disorder in which patients can present with nonautoimmune and non-HLA-linked diabetes mellitus followed by optic atrophy in the first decade; cranial diabetes insipidus and sensorineural deafness in the second decade; renal tract abnormalities early in the third decade; and multiple neurological abnormalities, such as cerebellar ataxia, myoclonus, and psychiatric illness early in the fourth decade.
- Wolfram syndrome patients usually die from central respiratory failure as a result of brainstem atrophy in their third or fourth decade. A large degree of inter-subject variability exists in the rate of progression.
- the clinical phenotype of Wolfram syndrome can show resemblance with mitochondrial disorders, such as maternally inherited diabetes and deafness, mitochondrial encephalopathy, mitochondrial myopathy, lactic acidosis and stroke-like episodes, or Leber’s hereditary optic neuropathy.
- WFS1 variants associated with Wolfram syndrome include missense, nonsense, frameshift, in-frame insertion or deletions, and splice-site variants.
- Variants of WFS1 are known in the art and described in e.g., van ven Ouweland JM, et al. Molecular characterization of WFS1 in patients with Wolfram syndrome. The Journal of molecular diagnostics 2003;5(2):88-95 and Khanim F, et al.
- WFS1/wolframin mutations WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Human mutation. 2001;17(5):357-67.
- WFS1 encodes an endoplasmic reticulum (ER) transmembrane protein.
- the ER is a network within all cells involved in protein synthesis, calcium storage and handling, redox regulation, steroid synthesis, and cell signaling, including apoptotic signaling. Given the vital functions of the ER, its dysfunction can trigger a range of cellular pathologies. Studies have shown that pancreatic beta cells and neurons are particularly sensitive to ER dysfunction, potentially due to high rates of hormone and neurotransmitter synthesis, respectively.
- WFS1 can regulate Ca2+ homeostasis in the ER, which is crucial in the synthesis and secretion of neurotransmitters and hormones such as insulin.
- WFS1 deficiency in the ER causes Ca2+ homeostasis disruption, leading to chronic ER stress followed by the unfolded protein response (UPR).
- WFS1 also negatively regulates ATF6, a UPR molecule, inhibiting hyperactivation of ATF6 and consequent cell apoptosis.
- WFS1 can impact mitochondrial function by transporting Ca2+ from the ER to the mitochondria via the mitochondria-associated ER membrane (MAM).
- MAM mitochondria-associated ER membrane
- pancreatic ⁇ cells and neuronal cells can be lost as a consequence of mutations in the WFS1 gene.
- WFS1 mutations lead to ER stress, pancreatic ⁇ cell dysfunction, and the initiation of ER-associated cell death.
- a small portion of patients have mutations in the WFS2 (CISD2) gene.
- WFS2 also encodes an ER transmembrane protein.
- diabetes mellitus and hearing impairment are reported.
- the clinical phenotype of these patients may differ from patients carrying WFS1 mutations with the absence of diabetes insipidus, the presence of upper intestinal ulcers and bleeding events, and defective platelet aggregation.
- the methods described herein can be used for treating a subject that exhibits one or more symptoms associated with Wolfram syndrome, or has been diagnosed with Wolfram syndrome.
- the subject may be suspected as having Wolfram syndrome, and/or at risk for developing Wolfram syndrome.
- the methods described herein can further include determining that a subject has or is at risk for developing Wolfram syndrome, diagnosing a subject as having or at risk for developing Wolfram syndrome, or selecting a subject having or at risk for developing Wolfram syndrome.
- a number of features, symptoms, and conditions are associated with Wolfram syndrome and can be used for diagnostic purposes.
- the subject can have or be at risk for developing diabetes mellitus.
- the subject can have or be at risk for developing juvenile-onset diabetes mellitus (e.g. with an onset age of ⁇ 15 years).
- the subject can have or be at risk for developing optic atrophy (e.g.
- high-tone sensorineural hearing impairment e.g., congenital hearing impairment
- cerebellar ataxia autonomic dysfunction
- dementia or intellectual disability e.g., psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction
- diabetes insipidus e.g., central diabetes insipidus
- delayed/absent puberty hypogonadism in males
- non-autoimmune hypothyroidism growth retardation
- cardiomyopathy structural congenital heart defects.
- Genetic testing approaches can include gene-targeted testing (single- gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
- sequence analysis of one or more genes involved in Wolfram syndrome e.g. WFS1, WFS2 or other genes known in the art
- WFS1 and other genes of interest can be performed as described in Tranebj ⁇ rg et al. (WFS1 Wolfram Syndrome Spectrum Disorder. 2009 Feb 24. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews®.
- Mutations in the WFS1 gene can include the H313Y mutation (Hansen L, Eiberg H, Barrett T, et al. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. Eur J Hum Genet. 2005;13(12):1275–84), p.Trp314Arg (Bonnycastle LL, Chines PS, Hara T, et al. Autosomal dominant diabetes arising from a wolfram syndrome mutation. Diabetes.
- the subject may have shown one or more symptoms of Wolfram syndrome (e.g. any symptoms of Wolfram syndrome described herein or known in the art) for about 1 day to about 5 years (e.g. about 1 to about 6 months, about 7 to about 18 months, or about 2, 3, or 4 years).
- the subject may have been diagnosed with Wolfram syndrome for about for about 1 day to about 5 years (e.g. about 1 to about 6 months, about 7 to about 18 months, or about 2, 3, or 4 years).
- the subject can be confirmed or identified, e.g.
- a healthcare professional as having Wolfram syndrome.
- Multiple parties may be included in the process of diagnosis. For example, where samples are obtained from a subject as part of a diagnosis, a first party can obtain a sample from a subject and a second party can test the sample.
- the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner). Skilled practitioners will appreciate that certain factors can affect the bioavailability and metabolism of the administered compounds for a subject, and can make adjustments accordingly. These include but are not limited to liver function (e.g. levels of liver enzymes), renal function, and gallbladder function (e.g., ion absorption and secretion, levels of cholesterol transport proteins).
- each subject has for the administered compounds (e.g., bile acid and a phenylbutyrate compound), differences in the levels of excretion, and in the pharmacokinetics of the compounds in the subjects being treated.
- Any of the factors described herein may affect drug exposure by the subject. For instance, decreased clearance of the compounds can result in increased drug exposure, while improved renal function can reduce the actual drug exposure.
- the extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment.
- the methods described herein can be used for preventative and prophylaxis purposes. II.
- compositions The present disclosure provides methods of treating at least one symptom of Wolfram syndrome in a subject, the methods including administering to the subject a bile acid or a pharmaceutically acceptable salt thereof and a phenylbutyrate compound.
- the methods include administering a composition comprising a TURSO and a sodium phenylbutyrate to a subject.
- Bile Acid refers to naturally occurring surfactants having a nucleus derived from cholanic acid substituted with a 3 ⁇ -hydroxyl group and optionally with other hydroxyl groups as well, typically at the C6, C7 or C12 position of the sterol nucleus.
- Bile acid derivatives e.g., aqueous soluble bile acid derivatives
- Bile acids conjugated with an amine are also encompassed by the term “bile acid”.
- Bile acid derivatives include, but are not limited to, derivatives formed at the carbon atoms to which hydroxyl and carboxylic acid groups of the bile acid are attached with other functional groups, including but not limited to halogens and amino groups.
- Soluble bile acids may include an aqueous preparation of a free acid form of bile acids combined with one of HCl, phosphoric acid, citric acid, acetic acid, ammonia, or arginine.
- Suitable bile acids include but are not limited to, taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also referred to as “chenodiol” or “chenic acid”), cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, or an analog, derivative, or prodrug thereof.
- the bile acids of the present disclosure are hydrophilic bile acids.
- Hydrophilic bile acids include but are not limited to, TURSO, UDCA, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid.
- Pharmaceutically acceptable salts or solvates of any of the bile acids disclosed herein are also contemplated.
- bases commonly employed to form pharmaceutically acceptable salts of the bile acids of the present disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2- hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino
- tauroursodeoxycholic acid (TUDCA) and “taurursodiol” (TURSO) are used interchangeably herein.
- the bile acid described herein can be TURSO, as shown in formula I (with labeled carbons to assist in understanding where substitutions may be made).
- the TURSO is a hydrate, such as TURSO dihydrate.
- the bile acid described herein can be UDCA as shown in formula II (with labeled carbons to assist in understanding where substitutions may be made). , or a pharmaceutically acceptable salt thereof.
- Derivatives of bile acids of the present disclosure can be physiologically related bile acid derivatives.
- bile acid can also be a bile acid conjugated with an amino acid.
- the amino acid in the conjugate can be, but are not limited to, taurine, glycine, glutamine, asparagine, methionine, or carbocysteine.
- amino acids that can be conjugated with a bile acid of the present disclosure include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, cysteine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan, as well as ⁇ -alanine, and ⁇ -aminobutyric acid.
- amino acid is a basic amino acid.
- amino acid include glycine, glutamine, asparagine, methionine, carbocysteine, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, cysteine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan, as well as ⁇ -alanine, and ⁇ -aminobutyric acid.
- a bile acid of the present disclosure is a compound of formula IV: wherein R is -H or C1-C4 alkyl; R 1 is -CH 2 -SO 3 R 3 , and R 2 is -H; or R1 is -COOH and R2 is -CH2-CH2-CONH2, -CH2-CONH2, -CH2-CH2-SCH3, or - CH2-S-CH2-COOH; and R 3 is -H or the residue of a basic amino acid, or a pharmaceutically acceptable analog, derivative, prodrug thereof, or a mixture thereof.
- basic amino acids include lysine, histidine, and arginine.
- the bile acid is TURSO.
- TURSO is an ambiphilic bile acid and is the taurine conjugate form of UDCA. TURSO recovers mitochondrial bioenergetic deficits through incorporating into the mitochondrial membrane, reducing Bax translocation to the mitochondrial membrane, reducing mitochondrial permeability, and increasing the apoptotic threshold of the cell (Rodrigues et al. Biochemistry 42, 10: 3070-3080, 2003). It is used for the treatment of cholesterol gallstones, where long periods of treatment is generally required (e.g., 1 to 2 years) to obtain complete dissolution.
- TURSO is contraindicated in subjects with biliary tract infections, frequent biliary colic, or in subjects who have trouble absorbing bile acids (e.g. ileal disease or resection).
- Drug interactions may include with substances that inhibit the absorption of bile acids, such as cholestyramine, and with drugs that increase the elimination of cholesterol in the bile (TURSO reduces biliary cholesterol content).
- the bile acid is UDCA.
- UDCA or ursodiol, has been used for treating gallstones, and is produced and secreted endogenously by the liver as a taurine (TURSO) or glycine (GUDCA) conjugate. Taurine conjugation increases the solubility of UDCA by making it more hydrophilic.
- TURSO is taken up in the distal ileum under active transport and therefore likely has a slightly a longer dwell time within the intestine than UDCA which is taken up more proximally in the ileum.
- Ursodiol therapy has not been associated with liver damage. Abnormalities in liver enzymes have not been associated with Actigall® (Ursodiol USP capsules) therapy and, Actigall® has been shown to decrease liver enzyme levels in liver disease. However, subjects given Actigall® should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.
- bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption.
- Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents.
- Estrogens, oral contraceptives, and clofibrate increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.
- Phenylbutyrate compounds is defined herein as encompassing phenylbutyrate (a low molecular weight aromatic carboxylic acid) as a free acid (4-phenylbutyrate (4-PBA), 4- phenylbutyric acid, or phenylbutyric acid), and pharmaceutically acceptable salts, co-crystals, polymorphs, hydrates, solvates, conjugates, derivatives or pro-drugs thereof.
- Phenylbutyrate compounds described herein also encompass analogs of 4-PBA, including but not limited to Glyceryl Tri-(4-phenylbutyrate), phenylacetic acid (which is the active metabolite of PBA), 2- (4-Methoxyphenoxy) acetic acid (2-POAA-OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA- NO2), and 2-(2-Naphthyloxy) acetic acid (2-NOAA), and their pharmaceutically acceptable salts.
- Phenylbutyrate compounds also encompass physiologically related 4-PBA species, such as but not limited to any substitutions for Hydrogens with Deuterium in the structure of 4-PBA.
- HDAC2 inhibitors are contemplated herein as substitutes for phenylbutyrate compounds.
- Physiologically acceptable salts of phenylbutyrate include, for example sodium, potassium, magnesium or calcium salts.
- Other example of salts include ammonium, zinc, or lithium salts, or salts of phenylbutyrate with an orgain amine, such as lysine or arginine.
- the phenylbutyrate compound is sodium phenylbutyrate.
- Phenylbutyrate is a pan-HDAC inhibitor and can ameliorate ER stress through upregulation of the master chaperone regulator DJ-1 and through recruitment of other chaperone proteins (See e.g., Zhou et al. J Biol Chem. 286: 14941-14951, 2011 and Suaud et al. JBC. 286:21239-21253, 2011).
- the large increase in chaperone production reduces activation of canonical ER stress pathways, folds misfolded proteins, and has been shown to increase survival in in vivo models including the G93A SOD1 mouse model of ALS (See e.g., Ryu, H et al. J Neurochem.
- Formulation Bile acids and phenylbutyrate compounds described herein can be formulated for use as or in pharmaceutical compositions.
- the methods described herein can include administering an effective amount of a composition comprising TURSO and sodium phenylbutyrate.
- effective amount refer to an amount or a concentration of one or more drugs administered for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome.
- the composition can include about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO and about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate.
- the composition includes about 9.7% w/w of TURSO and 29.2% w/w of sodium phenylbutyrate.
- the sodium phenylbutyrate and TURSO can be present in the composition at a ratio by weight of between about 1:1 to about 4:1 (e.g., about 2:1 or about 3:1). In some embodiments, the ratio between sodium phenylbutyrate and TURSO is about 3:1.
- the compositions described herein can include any pharmaceutically acceptable carrier, adjuvant, and/or vehicle.
- pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound disclosed herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
- pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
- the pharmaceutical compositions may contain any conventional non-toxic pharmaceutically- acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- compositions of the present disclosure can include about 8% to about 24% w/w of dextrates (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6% w/w of dextrates).
- dextrates of the present disclosure can include a mixture of saccharides developed from controlled enzymatic hydrolysis of starch.
- compositions described herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra).
- Compositions of the present disclosure can include about 1% to about 6% w/w of sugar alcohol (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w of sugar alcohol).
- Sugar alcohols can be derived from sugars and contain one hydroxyl group (-OH) attached to each carbon atom. Both disaccharides and monosaccharides can form sugar alcohols.
- Sugar alcohols can be natural or produced by hydrogenation of sugars.
- Exemplary sugar alcohols include but are not limited to, sorbitol, xylitol, and mannitol.
- the composition comprises about 1% to about 6% w/w (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w) of sorbitol.
- Compositions of the present disclosure can include about 22% to about 35% w/w of maltodextrin (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w/w, e.g., about 28.3% w/w of maltodextrin).
- Maltodextrin can form a flexible helix enabling the entrapment of the active ingredients (e.g., any of the phenylbutyrate compounds and bile acids described herein) when solubilized into solution, thereby masking the taste of the active ingredients.
- Maltodextrin produced from any suitable sources are contemplated herein, including but not limited to, pea, rice, tapioca, corn, and potato.
- the maltodextrin is pea maltodextrin.
- the composition includes about 28.3% w/w of pea maltodextrin.
- pea maltodextrin obtained from Roquette KLEPTOSE® LINECAPS
- compositions described herein can further include sugar substitutes (e.g. sucralose).
- sugar substitutes e.g. sucralose
- the compositions can include about 0.5% to about 5% w/w of sucralose (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w/w of sucralose).
- Other sugar substitutes contemplated herein include but are not limited to aspartame, neotame, acesulfame potassium, saccharin, and advantame.
- the compositions include one or more flavorants.
- compositions can include about 2% to about 15% w/w of flavorants (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w).
- Flavorants can include substances that give another substance flavor, or alter the characteristics of a composition by affecting its taste. Flavorants can be used to mask unpleasant tastes without affecting physical and chemical stability, and can be selected based on the taste of the drug to be incorporated. Suitable flavorants include but are not limited to natural flavoring substances, artificial flavoring substances, and imitation flavors. Blends of flavorants can also be used.
- compositions described herein can include two or more (e.g., two, three, four, five or more) flavorants.
- Flavorants can be soluble and stable in water. Selection of suitable flavorants can be based on taste testing. For example, multiple different flavorants can be added to a composition separately, which are subjected to taste testing.
- Exemplary flavorants include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry or mixed berry flavor powder).
- compositions described herein can include about 0.5% to about 1.5% w/w (e.g., about 1% w/w) of a mixed berry flavor powder and/or about 5% to about 7% w/w (e.g., about 6.3% w/w) of a masking flavor. Suitable masking flavors can be obtained from e.g., Firmenich.
- the compositions described herein can further include silicon dioxide (or silica). Addition of silica to the composition can prevent or reduce agglomeration of the components of the composition. Silica can serve as an anti-caking agent, adsorbent, disintegrant, or glidant.
- the compositions described herein include about 0.1% to about 2% w/w of porous silica (e.g., about 0.3% to about 1.5%, about 0.5% to about 1.2%, or about 0.8% to about 1%, e.g., 0.9% w/w).
- Porous silica may have a higher H 2 O absorption capacity and/or a higher porosity as compared to fumed silica, at a relative humidity of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher).
- the porous silica can have an H 2 O absorption capacity of about 5% to about 40% (e.g. about 20% to about 40%, or about 30% to about 40%) by weight at a relative humidity of about 50%.
- the porous silica can have a higher porosity at a relative humidity of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher) as compared to that of fumed silica.
- the porous silica have an average particle size of about 2 ⁇ m to about 10 ⁇ m (e.g. about 3 ⁇ m to about 9 ⁇ m, about 4 ⁇ m to about 8 ⁇ m, about 5 ⁇ m to about 8 ⁇ m, or about 7.5 ⁇ m).
- the porous silica have an average pore volume of about 0.1 cc/gm to about 2.0 cc/gm (e.g., about 0.1 cc/gm to about 1.5 cc/gm, about 0.1 cc/gm to about 1 cc/gm, about 0.2 cc/gm to about 0.8 cc/gm, about 0.3 cc/gm to about 0.6 cc/gm, or about 0.4 cc/gm).
- the porous silica have a bulk density of about 50 g/L to about 700 g/L (e.g.
- compositions described herein include about 0.05% to about 2% w/w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace).
- the compositions described herein can further include one or more buffering agents.
- the compositions can include about 0.5% to about 5% w/w of buffering agents (e.g., about 1% to about 4% w/w, about 1.5% to about 3.5% w/w, or about 2% to about 3% w/w, e.g. about 2.7% w/w of buffering agents).
- Buffering agents can include weak acid or base that maintain the acidity or pH of a composition near a chosen value after addition of another acid or base. Suitable buffering agents are known in the art.
- the buffering agent in the composition provided herein is a phosphate, such as a sodium phosphate (e.g., sodium phosphate dibasic anhydrous).
- the composition can include about 2.7% w/w of sodium phosphate dibasic.
- the compositions can also include one or more lubricants.
- the compositions can include about 0.05% to about 1% w/w of lubricants (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8 %, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g. about 0.5% w/w of lubricants).
- Exemplary lubricants include, but are not limited to sodium stearyl fumarate, magnesium stearate, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, polyethylene glycols, alkyl sulphates, glyceryl behenate, and hydrogenated oil. Additional lubricants are known in the art.
- the composition includes about 0.05% to about 1% w/w (e.g., any of the subranges of this range described herein) of sodium stearyl fumarate.
- the composition can include about 0.5% w/w of sodium stearyl fumarate.
- the composition include about 29.2% w/w of sodium phenylbutyrate, about 9.7% w/w of TURSO, about 15.6% w/w of dextrates, about 3.9% w/w of sorbitol, about 1.9% w/w of sucralose, about 28.3% w/w of maltodextrin, about 7.3% w/w of flavorants, about 0.9% w/w of silicon dioxide, about 2.7% w/w of sodium phosphate (e.g. sodium phosphate dibasic), and about 0.5% w/w of sodium stearyl fumerate.
- sodium phosphate e.g. sodium phosphate dibasic
- the composition can include about 3000 mg of sodium phenylbutyrate, about 1000 mg of TURSO, about 1600 mg of dextrates, about 400 mg of sorbitol, about 200 mg of sucralose, about 97.2 mg of silicon dioxide, about 2916 mg of maltodextrin, about 746 mg of flavorants (e.g. about 102 mg of mixed berry flavor and about 644 mg of masking flavor), about 280 mg of sodium phosphate (e.g. sodium phosphate dibasic), and about 48.6 mg of sodium stearyl fumerate.
- compositions such as but not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solid.
- Water soluble artificial sweeteners are contemplated herein, such as the soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamate salts, acesulfam potassium (acesulfame K), and the free acid form of saccharin and aspartame based sweeteners such as L-aspartyl- phenylalanine methyl ester, Alitame® or Neotame®.
- the amount of sweetener or taste masking agents can vary with the desired amount of sweeteners or taste masking agents selected for a particular final composition.
- Pharmaceutically acceptable binders in addition to those described above are also contemplated.
- Examples include cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g. Primogel® and Explotab®).
- croscarmellose sodium i.e. cross-linked carboxymethylcellulose sodium salt
- alginic acid or alginates alginic acid or alginates
- insoluble polyvinylpyrrolidone e.g. Polyvidon® CL, Polyvidon®
- Additional fillers, diluents or binders may be incorporated such as polyols, sucrose, sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g., spray-dried lactose, ⁇ -lactose, ⁇ - lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floc®), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka- Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g.
- the compositions described herein can be formulated or adapted for administration to a subject via any route (e.g. any route approved by the Food and Drug Administration (FDA)).
- FDA Food and Drug Administration
- compositions are typically formulated to be compatible with its intended route of administration.
- routes of administration include parenteral (subcutaneous, intracutaneous, intravenous, intradermal, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation or through a feeding tube), transdermal (topical), transmucosal, and rectal administration.
- compositions can be in the form of a solution or powder for inhalation and/or nasal administration.
- the pharmaceutical composition is formulated as a powder filled sachet.
- Suitable powders may include those that are substantially soluble in water.
- Pharmaceutical compositions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- Suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- a long-chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- the compositions can be orally administered in any orally acceptable dosage form including, but not limited to, powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- the powders can be substantially dissolved in water prior to administration.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, may be added.
- useful diluents include lactose and dried corn starch.
- the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- the compositions can be administered by nasal aerosol or inhalation.
- compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- therapeutic compositions disclosed herein can be formulated for sale in the US, imported into the US, and/or exported from the US.
- the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
- the invention provides kits that include the bile acid and phenylbutyrate compounds.
- the kit may also include instructions for the physician and/or patient, syringes, needles, box, bottles, vials, etc. III.
- Methods of treatment The present disclosure provides methods of treating one or more symptoms of Wolfram syndrome in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a combination of a bile acid compound or a pharmaceutically acceptable salt there of (e.g. TURSO) and a phenylbutyrate compound (e.g. sodium phenylbutyrate).
- a bile acid or a pharmaceutically acceptable salt thereof and the phenylbutyrate compound can be administered separately or concurrently, including as a part of a regimen of treatment.
- the compounds can be administered daily (e.g.
- the compounds can be administered over a period of weeks, months, or years.
- the compounds can be administered over a period of at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more.
- the compounds can be administered once a day or twice a day for 60 days or less (e.g., 55 days, 50 days, 45 days, 40 days, 35 days, 30 days or less).
- the bile acid and phenylbutyrate compound can be administered once a day or twice a day for more than 60 days (e.g., more than 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 180, 200, 250, 300, 400, 500, 600 days).
- TURSO can be administered at an amount of about 0.5 to about 5 grams per day (e.g., about 0.5 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 0.5 to about 3, about 0.5 to about 2.5, about 0.5 to about 2, about 0.5 to about 1.5, about 0.5 to about 1, about 1 to about 5, about 1 to about 4.5, about 1 to about 4, about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 5, about 1.5 to about 4.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 5, about 2 to about 4.5, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 5, about 2.5 to about 4.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 5, about 3 to about 4.5, about 3 to about 4, about 3 to about 3.5, about
- TURSO is administered at an amount of about 1 to about 2 grams per day (e.g., about 1 to about 1.8 grams, about 1 to about 1.6 grams, about 1 to about 1.4 grams, about 1 to about 1.2 grams, about 1.2 to about 2.0 grams, about 1.2 to about 1.8 grams, about 1.2 to about 1.6 grams, about 1.2 to about 1.4 grams, about 1.4 to about 2.0 grams, about 1.4 to about 1.8 grams, about 1.4 to about 1.6 grams, about 1.6 to about 2.0 grams, about 1.6 to about 1.8 grams, about 1.8 to about 2.0 grams).
- TURSO is administered at an amount of about 1 gram per day.
- TURSO can be administered at an amount of about 1 gram once a day.
- TURSO is administered at an amount of about 2 grams per day.
- TURSO can be administered at an amount of about 1 gram twice a day.
- Sodium phenylbutyrate can be administered at an amount of about 0.5 to about 10 grams per day (e.g., about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2.5 to about 9.5, about 2.5 to about 8.5, about 2.5 to about 7.5, about 2.5 to about 6.5, about 2.5 to about 5.5, about 2.5 to about 4.5, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6.5, about 3 to about 6, about 3 to about 5, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to
- sodium phenylbutyrate is administered at an amount of about 3 to about 6 grams per day (e.g., about 3 to about 5.5 grams, about 3 to about 5.0 grams, about 3 to about 4.5 grams, about 3 to about 4.0 grams, about 3 to about 3.5 grams, about 3.5 to about 6 grams, about 3.5 to about 5.5 grams, about 3.5 to about 5.0 grams, about 3.5 to about 4.5 grams, about 3.5 to about 4.0 grams, about 4.0 to about 6 grams, about 4.0 to about 5.5 grams, about 4.0 to about 5.0 grams, about 4.0 to about 4.5 grams, about 4.5 to about 6 grams, about 4.5 to about 5.5 grams, about 4.5 to about 5.0 grams, about 5.0 to about 6 grams, about 5.0 to about 5.5 grams, or about 5.5 to about 6.0 grams).
- about 3 to about 6 grams per day e.g., about 3 to about 5.5 grams, about 3 to about 5.0 grams, about 3 to about 4.5 grams, about 3 to about 4.0 grams, about 3 to about 3.5
- sodium phenylbutyrate is administered at an amount of about 3 grams per day.
- sodium phenylbutyrate can be administered at an amount of about 3 grams once a day.
- sodium phenylbutyrate is administered at an amount of about 6 grams per day.
- sodium phenylbutyrate can be administered at an amount of about 3 grams twice a day.
- the bile acid and phenylbutyrate compound are administered at a ratio by weight of about 2.5:1 to about 3.5:1 (e.g., about 3:1).
- the methods described herein can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day, or about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day.
- the methods can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day for at least about 14 days (e.g., at least about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 30, 35, or 40 days), followed by administering about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day for at least a day (e.g.
- the methods can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day for about 14-21 days, followed by administering about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day.
- the methods described herein include administering to a subject about 5 mg/kg to about 100 mg/kg of body weight of TURSO (e.g.
- about 10 to about 50 about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 75, about 75 to about 80, about 80 to about 85, about 85 to about 90, about 90 to about 95, or about 95 to about 100 mg/kg).
- the methods described herein include administering to a subject about 10 mg/kg to about 400 mg/kg of body weight of sodium phenylbutyrate (e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300 to about 400 mg/kg).
- sodium phenylbutyrate e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300
- TURSO is administered in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of body weight.
- sodium phenylbutyrate is administered in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or 150 mg/kg of body weight.
- the methods can be used to treat subjects who display one or more conditions including, e.g., diabetes insipidus, diabetes mellitus (e.g. juvenile-onset diabetes), optic nerve atrophy, progressive neurodegeneration, hearing loss, endocrine deficiencies and neurological and psychiatric conditions, cerebellar ataxia, autonomic dysfunction, dementia or intellectual disability, psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction, delayed/absent puberty, hypogonadism in males, non-autoimmune hypothyroidism, growth retardation, cardiomyopathy or structural congenital heart defects.
- the subject has or is at risk for developing diabetes, for example, insulin-dependent diabetes or juvenile onset diabetes.
- the subject has or is at risk for developing optic nerve atrophy or a hearing impairment.
- the subject has one or more mutations in the WFS1 gene.
- the subject may have the c.1672C>T, p.R558C mutation in the WFS1 gene or the c.2654C>T, p.P885L mutation in the WFS1 gene.
- the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene.
- administration of the combination of the bile acid compound (e.g. TURSO) and the phenylbutyrate compound e.g.
- sodium phenylbutyrate results in improved treatment of one or more symptoms of Wolfram syndrome as compared to each compound alone.
- treatment with a combination of TURSO and sodium phenylbutyrate can lead to symptom reduction for the subjects described herein to a greater extent or at a faster rate than each compound alone.
- Methods described in the present disclosure can include treatment of Wolfram syndrome per se, as well as treatment for one or more symptoms of Wolfram syndrome. “Treating” Wolfram syndrome does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity of symptoms or features of the disease is contemplated.
- Treating” Wolfram syndrome also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease. “Treating” Wolfram syndrome also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating Wolfram syndrome disclosed herein or known in the art). “Treating” Wolfram syndrome also refers to eliminating or reducing one or more direct or indirect effects of Wolfram syndrome disease progression. The subject may not exhibit signs of Wolfram syndrome but may be at risk for Wolfram syndrome. For instance, the subject may carry mutations in genes associated with Wolfram syndrome, have family history of having Wolfram syndrome.
- the subject may exhibit early signs of the disease or display symptoms of established or progressive disease.
- the disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms.
- the treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing Wolfram syndrome), at symptom onset or immediately following detection of Wolfram syndrome symptoms, upon observation of any one or more symptoms that would lead a skilled practitioner to suspect that the subject may be developing Wolfram syndrome. Treatment can also be initiated at later stages. For example, treatment may be initiated at progressive stages of the disease.
- Treatment methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of Wolfram syndrome, or at least one symptom of Wolfram syndrome.
- the duration of prophylaxis treatment can be a single dosage or the treatment may continue (e.g., multiple dosages), e.g., for years or indefinitely for the lifespan of the subject.
- a subject at risk for Wolfram syndrome may be treated with the methods provided herein for days, weeks, months, or even years so as to prevent the disease from occurring or fulminating.
- treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment.
- the treatment provided herein can be administered one or more times daily, or it can be administered weekly or monthly.
- treatment can continue until a decrease in the level of disease in the subject is detected.
- administer refers to administering drugs described herein to a subject using any art-known method, e.g., ingesting, injecting, implanting, absorbing, or inhaling, the drug, regardless of form.
- one or more of the compounds disclosed herein can be administered to a subject by ingestion orally and/or topically (e.g., nasally).
- the methods herein include administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
- Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
- the subject can be evaluated to detect, assess, or determine their level of Wolfram syndrome disease.
- treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.
- a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- the methods described herein can further include administering to the subject one or more additional therapeutic agents, e.g. in amounts effective for treating or achieving a modulation of at least one symptom of Wolfram syndrome. Any Wolfram syndrome therapeutic agents known in the art can be used as an additional therapeutic agent.
- Exemplary therapeutic agents include valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, and ER Ca2+ stabilizer.
- GLP glucagon-like peptide
- the bile acid or a pharmaceutically acceptable salt thereof and the phenylbutyrate compound can be administered shortly after a meal (e.g., within two hours of a meal) or under fasting conditions.
- the subject may have consumed food items (e.g., solid foods or liquid foods) less than 2 hours before administration of a bile acid or a pharmaceutically acceptable salt thereof and/or a phenylbutyrate compound; or will consume food items less than 2 hours after administration of one or both of the compounds.
- Food items may affect the rate and extent of absorption of the bile acid or a pharmaceutically acceptable salt thereof and/or the phenylbutyrate compound.
- food can change the bioavailability of the compounds by delaying gastric emptying, stimulating bile flow, changing gastrointestinal pH, increasing splanchnic blood flow, changing luminal metabolism of the substance, or physically or chemically interacting with a dosage form or the substance.
- the nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiological changes in the GI tract in a way that affects drug transit time, luminal dissolution, drug permeability, and systemic availability.
- the methods provided herein can further include administering to the subject a plurality of food items, for example, less than 2 hours (e.g., less than 1.5 hour, 1 hour, or 0.5 hour) before or after administering the bile acid or a pharmaceutically acceptable salt thereof, and/or the phenylbutyrate compound.
- a plurality of food items for example, less than 2 hours (e.g., less than 1.5 hour, 1 hour, or 0.5 hour) before or after administering the bile acid or a pharmaceutically acceptable salt thereof, and/or the phenylbutyrate compound.
- PBMCs peripheral blood mononuclear cells
- ER stress marker genes BiP and spliced XBP1 (sXBP1)
- sXBP1 ER stress marker genes
- CHOP and TXNIP ER stress- induced apoptosis genes
- OCRs oxygen consumption rates
- AMX0035 inhibited apoptosis, as indicated by caspase 3/7 activity, in each of the three patient lines.
- AMX0035 treatment mitigated cellular stress increased by pathogenic WFS1 variants without changing ⁇ cell identity, which resulted in increased ⁇ cell and insulin secretion in W024 and W121 SC- ⁇ cells.
- delays in the Wolfram diabetic phenotype in Wfs1 KO mice when using the AMX0035 chow were observed.
- Results Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development.
- p.R558C variant show mild forms of Wolfram syndrome phenotypes.
- Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome.
- Human induced pluripotent stem cell (iPSC)-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulate genotype-related Wolfram syndrome phenotypes.
- Enhancing residual WFS1 function by a combination treatment of chemical chaperones mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increases insulin secretion in SC-islets.
- the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones.
- WFS1 c.1672C>T WFS1 c.1672C>T
- p.R558C is enriched in Ashkenazi Jewish population and causes a mild form of Wolfram phenotypes
- Ashkenazi, Sephardi, Ashkenazi/Sephardi 87,093 subjects from several Jewish populations.
- each subject was classified by self-identification as Ashkenazi, Sephardi, Ashkenazi/Sephardi, Convert, and Unknown. Samples from Converts and Unknown origin made up a total of 773 and were excluded from analysis.
- WFS1 p.R558C variant is degraded more than wild-type, but less than WFS1 p.P885L variant
- Pathogenic WFS1 variants are classified based on their effect on WFS1 expression: class A, depleted WFS1 protein or reduced, defective WFS1 protein, which leads to loss-of- function or incomplete function; class B, expression of defective WFS1 protein leading to gain-of-function.
- Class A is furthermore divided into three subclasses: class A1, WFS1 depletion due to WFS1 mRNA degradation (nonsense mediated decay, NMD); class A2, WFS1 depletion due to WFS1 protein degradation; class A3, WFS1 depletion due to mRNA and protein degradation (de Heredia ML, et al.
- the p.R558C variant showed less thermal stability than wild-type WFS1, suggesting an altered folding state, but more stability compared to the known autosomal recessive variant p.P885L which is pathogenic and is associated with a typical form of Wolfram syndrome (Hardy C, et al. Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. American journal of human genetics. 1999;65(5):1279-90.; Qian X, et al. Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. Scientific reports. 2015;5:14731.) (FIG. 3A and B).
- Both p.R558C and p.P885L expression could be rescued by incubating cells at reduced temperature, supporting a folding defect conferred by the variants (FIG. 3C).
- Treatment with a proteasome inhibitor, bortezomib increased WFS1 protein levels from both variants and the fold change for p.P885L was higher than p.R558C (FIG. 3D), indicating that proteasomal degradation of p.R558C is less than p.P885L.
- CHX cycloheximide
- PBMCs peripheral blood mononuclear cells
- a combination treatment of 4-PBA and TUDCA ameliorates cellular function in neural progenitor cells with c.1672C>T, p.R558C variant
- P+T 4-PBA and TUDCA
- the incubation with P+T significantly increased the steady-state levels of WFS1 p.R558C protein, but not WT nor a NanoLuc control expressed from an identical plasmid backbone (FIG. 4B).
- NPCs neural progenitor cells differentiated from iPSCs derived from patients with typical Wolfram syndrome.
- ER stress marker genes BiP and spliced XBP1 (sXBP1)
- CHOP an ER stress-induced apoptosis gene
- TXNIP ER stress-induced apoptosis gene
- WFS1 protein levels were significantly increased in W392 and W121 by the P+T treatment compared to a single treatment with each compound (FIG. 6A).
- the expression of ER stress-induced apoptosis genes was similar regardless of single or combination treatments in W024 and W392 NPCs, whereas only the P+T treatment significantly decreased ER stress-induced apoptosis gene expression in W121 (FIG. 6B).
- Mitochondrial DNA was not greatly changed by any single treatment in each of the three patient lines. Although we confirmed the increase of mitochondrial membrane potentials in W121 NPCs by the P+T treatment; it was not observed by a single treatment with each compound (FIG. 7B).
- a combination treatment of 4-PBA and TUDCA increased WFS1 expression and inhibited apoptosis by mitigating ER stress and mitochondrial dysfunction, which was beneficial more than a single treatment of either 4-PBA or TUDCA alone although there were some variabilities among cell lines.
- a combination treatment of 4-PBA and TUDCA improves insulin secretion and survival in SC- ⁇ cells with WFS1 c.1672C>T, p.R558C variant
- the majority of patients with Wolfram syndrome develop diabetes mellitus due to the pathogenic WFS1 variants causing detrimental effects in pancreatic ⁇ cells (Fonseca SG, et al.
- WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic ⁇ beta ⁇ -Cells.
- SC-islets stem cell–derived pancreatic islets
- W024 and W121 iPSCs W024 and W121 iPSCs
- AN1.1 iPSCs a control.
- SC-islets stem cell–derived pancreatic islets
- SC- ⁇ insulin- positive stem cell-derived ⁇
- SC- ⁇ glucagon-positive stem cell-derived ⁇
- SC- ⁇ somatostatin-positive stem cell-derived ⁇
- the W024 and W121 Stage 6 SC- islets produced C-peptide+ cells co-expressing ⁇ cell differentiation marker (NKX6.1) and committed endocrine cell marker (CHGA).
- the ⁇ cell population was similar between W024 and control SC-islets, but reduced in the W121 line (FIG. 9A and B).
- WFS1 protein was expressed in SC-islets derived from all three lines, with greater expression detected in control SC-islets (FIG. 9C).
- WFS1 protein level was significantly higher in W024 SC-islets when compared to W121 (FIG. 9C).
- both patient-derived SC-islets showed a significant reduction of WFS1 mRNA levels (FIG.
- P+T treatment restored WFS1 expression and increased insulin secretion capabilities of W024 and W121 SC-islets.
- Cellular stress is mitigated by a combination treatment of 4-PBA and TUDCA in SC-islets with WFS1 c.1672C>T, p.R558C variant
- scRNA-seq multiplexed single-cell RNA sequencing
- 10x Genomics platform to investigate genotype-phenotype correlations and an efficacy of the P+T combination treatment on SC- ⁇ cells more precisely.
- We utilized Cell Hashing which applied oligo-tagged antibodies to the cell surface proteins of individual samples, thus allowing for detection of individual samples within a pooled cell population.
- the cell types were identified by aligning the top upregulated genes in each cell cluster population with published pancreatic transcriptome data. After identifying the ⁇ cell population in each sample, we combined the 2,329 SC- ⁇ cells from the four experimental conditions (W024: 377 cells, W024, P+T: 220 cells, W121: 749 cells, and W121, P+T: 680 cells) and performed Principal Component Analysis (PCA) and unsupervised clustering. The ⁇ cells clustered together based on genetic background, regardless of combination treatment, suggesting the ⁇ cell transcriptional profile was not greatly changed in response to P+T. MT1X and ERO1B were highly expressed in W121 SC- ⁇ cells treated with P+T compared to untreated.
- PCA Principal Component Analysis
- GSEA gene set enrichment analysis
- Wfs1 KO mice This mouse model develops progressive glucose intolerance during adolescence, hence a mouse model of Wolfram syndrome (Abreu D, et al. Wolfram syndrome 1 gene regulates pathways maintaining beta- cell health and survival. Laboratory investigation; a journal of technical methods and pathology. 2020;100(6):849-62.).
- Wfs1 KO mice developed glucose intolerance at 5-6 weeks old (FIG. 11A and 11B).
- Wfs1 KO mice did not show glucose-stimulated increase of the serum insulin level, which was lower than that of WT (FIG. 12A).
- mice We treated the mice at 5-6 weeks old with food containing 4-PBA and TUDCA (4-PBA: 0.338% and TUDCA: 0.225%, refer to P+T chow) for one month. Both groups of Wfs1 KO mice consumed similar amount of chow. After feeding for one month, Wfs1 KO mice fed with control chow developed more severe glucose intolerance (FIG. 11A and 11B). Conversely, an intraperitoneal glucose tolerance test (IP-GTT) blood glucose curve was similar to the baseline outcome in Wfs1 KO mice fed with P+T chow (FIG. 11A and 11B), indicating that P+T chow delayed the progression of the diabetic phenotype.
- IP-GTT intraperitoneal glucose tolerance test
- Example 2 A Phase II Study of Safety and Efficacy of AMX0035 in Adult Patients with Wolfram Syndrome Study Design: Single-centre, open-label study where up to 12 participants are treated with AMX0035 for up to 24 weeks. The study consists of a Screening period of up to 4 weeks, a 24-week Open-Label Treatment Period, and a post-treatment follow-up visit at Week 28. Upon completion of Screening and Baseline procedures, eligible participants will receive standard of care + AMX0035 at predefined doses.
- Eligible participants are enrolled into the Open-Label Treatment Period of the study on Day 1 and receive their first dose of study drug. During the first 3 weeks of dosing, participants take 1 sachet of AMX0035 daily and if tolerated will increase to 1 sachet twice daily (morning and evening). Participants will return to the study site every approximately 12 weeks for study procedures and assessments, and blood collection.
- the participant has a definitive diagnosis of Wolfram syndrome, as determined by the following: a. Documented functionally relevant recessive mutations on both alleles of the WFS1 gene based on historical test results (if available) or from a qualified laboratory at Screening. 2. A stimulated C-peptide level of ⁇ 0.2 ng/mL during the Screening Visit 3. Insulin dependent diabetes mellitus due to Wolfram syndrome 4. At least 17 years of age at the time of written informed consent 5. Women of child-bearing potential (e.g., not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control* for the duration of the study and 6 months after last dose of study drug.
- Hormonal methods such as birth control pills, patches, injections, vaginal ring, or implants
- Barrier methods such as a condom or diaphragm
- spermicide a foam, cream, or gel that kills sperm
- IUD Intrauterine device
- Abstinence no heterosexual sex
- Unique partner who is surgically sterile (men) or not of childbearing potential (female)
- Exclusion Criteria 1.
- Clinically significant non-Wolfram related central nervous system (CNS) involvement which is judged by the Investigator to likely interfere with the accurate administration and interpretation of protocol assessments 2.
- Clinically significant unstable medical condition other than Wolfram syndrome
- Clinically significant in the opinion of the Investigator, infection or inflammation at the time of Screening or admission. If infection and inflammation has been cured, participants can be rescreened 4.
- Acute gastrointestinal symptoms e.g., nausea, vomiting, diarrhea
- Abnormal liver function defined as aspartate transaminase (AST) and/or alanine transaminase (ALT) > 3 times the upper limit of the normal (ULN) 10.
- Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) ⁇ 60 mL/min/1.73 m 2 11.
- Anemia with hemoglobin (Hgb) concentration ⁇ 10.0 g/dL at screening 12.
- Previous treatment with gene or cellular therapy 20. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory determinations beyond what is consistent with the target population in the opinion of the PI. 21. Clinically significant abnormality on 12-lead ECG prior to study treatment administration, confirmed by repeat. 22. Any history of clinically significant suicidal ideation and/or behavior within 1 year of Screening as determined by the Investigator. 23. Anything that, in the opinion of the Investigator, precludes the participant's full compliance with or completion of the study 24. Currently or previously treated within the last 30 days prior to Screening or planned exposure to any prohibited medications listed below.
- AMX0035 All participants will receive oral AMX0035 treatment. For the first 3 weeks of dosing, participants will take 1 sachet daily and if tolerated will increase to 1 sachet twice daily (morning and evening). AMX0035 will be supplied by the Sponsor to the site pharmacy as a carton box containing single use sachets. Each AMX0035 sachet contains active ingredients (3 g PB and 1 g taurursodiol [TURSO]) and excipients in a powder formulation. Study drug is mixed with ⁇ 1 cup of water and taken orally. Duration of Study and Treatment: Treatment will last up to 24 weeks. The planned overall study duration is up to 32 weeks for participants who complete the study.
- TEAE treatment-emergent adverse events
- a participant demonstrates treatment-emergent signs of neurotoxicity including, but not limited to, vomiting, nausea, headache, dizziness, somnolence, dysgeusia hypoacusis, disorientation, confusion, memory loss, neuropathy, possibly related to study drug in the opinion of the Investigator, the Investigator should consider a dose reduction or interruption. Any dosage adjustment, including the reason for and dates of adjustment, will be documented in the source documentation and the electronic case report form (eCRF) Any dose modifications may be discussed with the Medical Monitor. The new regimen, reduced dose or interruption, may be maintained for as long as necessary until the event improves. The Investigator may then choose to resume the higher dosage or maintain the participant at a reduced dosage. Any dose interruptions should be discussed with the Medical Monitor.
- Treatment emergent increase in serum creatinine or liver enzymes according to the following guidance: o Confirmed increase > 50% from Baseline in serum creatinine o ALT or AST > 8 x ULN o ALT or AST > 5 x ULN for more than 2 weeks o ALT or AST > 3 x ULN and (serum total bilirubin > 2 x ULN or international normalized ratio > 1.5) o ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) ⁇ Treatment emergent Grade 3 AE per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 unless otherwise specified.
- CCAE Common Terminology Criteria for Adverse Events
- the diagnostic tools and rating scales include the following: • 0-240 minutes MMTT (Primary Efficacy Endpoint) The MMTT tests measure residual ⁇ -cell functions (Buss 1982). The night before the MMTT, the participant will receive an evening dose of Lantus insulin and fast from midnight until the test at 8:00 AM.
- the mixed meal consists of 6 mL/kg (maximum 360 mL) of Boost Original (Institute Produits Nestlé S.A., Vevey, Switzerland).
- Boost Original Prior to the MMTT, participants should not take short-acting insulin, short-acting GLP-1 receptor agonists, metformin, and SGLT inhibitors ⁇
- the timeframe for consumption of Boost Original is within 5 minutes ⁇ Blood for glucose and C-peptide measurement will be drawn at Times -10, 0, 15, 30, 60, 90, 120, 180, and 240 minutes with ⁇ 5 minutes sample collection windows ⁇ If a participant’s fasting glucose exceeds 11.1 mmol/L, the test will not be performed, but fasting glucose and C-peptide will be obtained ⁇
- Participants using continuous subcutaneous insulin infusion (CSII) for their diabetes management should receive appropriate insulin adjustment leading up to the MMTT test ⁇
- Appropriate clinical safety measure should be put in place to ensure safety of the participants during the 4h MMTT.
- the PI and study staff is responsible for appropriate clinical monitoring over the entire study day duration, this includes safety monitoring (e.g. ketone monitoring) during the MMTT.
- safety monitoring e.g. ketone monitoring
- appropriate clinical safety measure should be put in place to ensure safety of the participants during the 4h MMTT.
- Diabetic Measurements The primary responsibility for diabetes management will remain with the treating or referring diabetes care provider, but the Investigator study team will provide close additional support through interaction by phone as needed. Diabetes management will be monitored by the Investigator study staff with phone calls between study visits as needed.
- Diabetic measurements will include: ⁇ fasting glucose, fasting proinsulin, AUC C-peptide/AUC-glucose, delta proinsulin
- the diabetic measurements will allow for the following: ⁇ continuous glucose monitoring (CGM) ⁇ tracking changes in total daily insulin dose ⁇ tracking the reduction of HbA1c • WURS
- CGM continuous glucose monitoring
- the behavioral domain is rated 0 – 3, with zero (0) corresponding to a normal behavior, and three (3) indicating the presence of a disorder of greater severity.
- SARA The Scale for the Rating and Assessment of Ataxia (Subramony 2007) is an 8-item performance-based scale, yielding a total score 0 (no ataxia) to 40 (most severe ataxia). The scores are based on participant performance of: 1) gait, 2) stance, 3) sitting, 4) speech disturbance, 5) finger chase, 6) nose-finger test, 7) fast alternating hand movements, 8) heel- shin slide.
- VFQ-25 The 25-Item National Eye Institute Visual Functioning Questionnaire (VFQ-25) is designed to measure vision-related functioning and the influence of vision-related problems.
- the VFQ-25 represents 11 vision-related constructs and contains up to 39 items, plus an additional single- item general health rating question. Scoring involves raw scores being converted to a 100-point scale with higher scores associated with worse performance.
- CGI-C The CGI-C rates improvement by 7 categories: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. These assessments are administered to the participant by the Site (Study PI). • PGI-C Participants will evaluate the change in their Wolfram syndrome-related symptoms since initiation of study drug by choosing one of seven responses. The PGI-C is a 7-point response scale.
- MBS Most Bothersome Symptom
- OCT optical Coherence Tomography
- C-SSRS is a systematically administered instrument developed to track suicidal AEs across a treatment study.
- the instrument is designed to assess suicidal behavior and ideation, track and assess all suicidal events, as well as the lethality of attempts. Additional features assessed include frequency, duration, controllability, reason for ideation, and deterrents.
- the C-SSRS is considered a low-burden instrument as it takes less than 5 minutes to administer. It is administered to the participant by the Investigator or qualified designee. Any participant noted to have suicidal ideation with plan within the prior month, either via answering "yes" to Questions 4 or 5 to the suicidal ideation portion of the C-SSRS or via clinical interview, will be evaluated immediately by the Investigator.
- the Medical Monitor and Sponsor will also be informed. Appropriate steps will be taken to protect the participant, including but not limited to possible discontinuation (decided by either the Investigator or Medical Monitor) from the study and referral for appropriate psychiatric care. Any such participant at Screening or on Day 1 will also be excluded from the study.
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Abstract
Provided herein are methods for treating at least one symptom of treating one or more symptoms of Wolfram syndrome in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a combination of a bile acid compound and a phenylbutyric compound.
Description
METHODS AND COMPOSITIONS FOR TREATING WOLFRAM SYNDROME TECHNICAL FIELD The present disclosure generally relates to compositions and methods for treating Wolfram syndrome. BACKGROUND Wolfram syndrome is a genetic disorder characterized by juvenile onset diabetes, progressive blindness, and neurodegeneration. There is currently no treatment to delay, halt, or reverse the progression of this disease. Accordingly, treatment methods for patients with Wolfram syndrome are needed. SUMMARY Provided herein are methods of treating one or more symptoms of Wolfram syndrome in a subject, comprising administering to the subject a pharmaceutically effective amount of a combination of TURSO and sodium phenylbutyrate. In some embodiments, the subject has or is at risk for developing diabetes. In some embodiments, the diabetes is insulin-dependent diabetes. In some embodiments, the diabetes is juvenile onset diabetes. In some embodiments, the subject has or is at risk for developing optic nerve atrophy. In some embodiments, the subject has or is at risk for developing a hearing impairment. In some embodiments, the subject has one or more mutations in the Wolframin (WFS1) gene. In some embodiments, the subject has the c.1672C>T, p.R558C mutation in the WFS1 gene. In some embodiments, the subject has the c.2654C>T, p.P885L mutation in the WFS1 gene. In some embodiments, the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene. In some embodiments, the TURSO and the sodium phenylbutyrate are administered once a day or twice a day. In some embodiments, TURSO is administered to the subject at a dose of about 5mg/kg to about 100 mg/kg. In some embodiments, sodium phenylbutyrate is administered to the subject at a dose of about 10mg/kg to about 400 mg/kg. In some embodiments, the TURSO is administered at an amount of about 0.5 to about 5 grams per day. In some embodiments, the sodium phenylbutyrate is administered at an amount of about 0.5 grams to about 10 grams per day. In some embodiments, the methods include administering to the subject 1 gram of TURSO and 3 grams of sodium phenylbutyrate once a day or twice a day. In some embodiments, the methods include administering to the subject 1 gram of TURSO once a day and 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering to the
subject about 1 gram of TURSO twice a day and 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the TURSO and the sodium phenylbutyrate are administered orally. In some embodiments, the TURSO and the sodium phenylbutyrate are formulated as a single powder formulation. In some embodiments, the methods further include administering one or more additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents is valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, or ER Ca2+ stabilizers. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1B Carrier frequencies and clinical manifestation of WFS1 c.1672C>T, p.R558C variant. (FIG 1A) Carrier frequencies for WFS1 c.1672C>T, p.R558C in subjects of Ashkenazi, Ashkenazi/Sephardi and Sephardi descent. (FIG 1B) Carrier frequencies for WFS1 c.1672C>T, p.R558C by country origin. FIG. 2 Classification of pathogenic WFS1 variants. A schematic of classification of
pathogenic WFS1 variants in terms of protein expression. FIGS. 3A-3H. WFS1 p.R558C is more stable in the cell compared to p.P885L variant (FIG. 3A) Diagram of WFS1 protein showing the location of two variants, R558C and P885L. (FIG. 3B) Thermal profiles of WFS1 variants (WT, R558C and P885L) measured using SplitLuc tagged reporters expressed in HEK293T cells (Data from 3 independent experiments). (FIG. 3C) Luminescence intensities of WFS1 variants in cells incubated at 30 and 37℃ for 24 hours (n=12, ***P<0.001 and ****P<0.0001 by unpaired t-test). (FIG. 3D) Fold change of luminescence intensities of WFS1 variants treated with proteasome inhibitor, bortezomib, for 24 hours (**P<0.01 and ***P<0.001 by unpaired t-test compared to untreated). (FIG. 3E) (Left) Representative blotting image of WFS1 (HA) and α-Tubulin in CHX chase assay. Lower panel of WFS1 (HA) is long-exposure image. (Right) A quantification of relative WFS1 protein level normalized with α-Tubulin. (n=3, *P<0.05, **P<0.01 and ****P<0.0001 by two-way ANOVA). (FIG. 3F) (Upper) Representative blotting image of WFS1 and α-Tubulin in iPSCs. (Lower) A quantification of relative WFS1 protein level normalized with α-Tubulin (n=3, **P<0.01 and ****P<0.0001 by one-way ANOVA compared to BJFF.6, †††P<0.001 and ††††P<0.0001 by one-way ANOVA compared to AN1.1, #P<0.05 and ##P<0.01 by one-way ANOVA). (FIG. 3G) Relative mRNA level of WFS1 in iPSCs. (n=7, ****P<0.0001 by one-way ANOVA compared to BJFF.6, ††††P<0.0001 by one-way ANOVA compared to AN1.1, #P<0.05 and ##P<0.01 by one-way ANOVA). (FIG. 3H) Relative mRNA level of WFS1 in ActD chase assay (n=3, *P<0.05 by one-way ANOVA compared to BJFF.6, ###P<0.001 by one-way ANOVA compared to AN1.1). FIGS. 4A-4H. A combination treatment with 4-PBA and TUDCA mitigates detrimental effect of WFS1 c.1672C>T, p.R558C variant (FIG. 4A) A schematic of Wolfram syndrome etiology and the targets to modulate by a combination treatment of 4-PBA and TUDCA (P+T). (FIG. 4B) Expression of HiBiT tagged WFS1 protein after treatment with 500 µM 4-PBA and 50 µM TUDCA (P+T) for 24 hours. NanoLuc levels, expressed from an identical plasmid backbone, were examined (n=48, P value by unpaired t-test). (FIG. 4C) (Left) Representative blotting images of WFS1 and α-Tubulin in iPSCs treated with or without P+T for 48 hours. (Right) A quantification of WFS1 protein levels normalized with α-Tubulin. (n=3, *P<0.05 and ***P<0.001 by unpaired t-test compared to Ctrl). (FIG. 4D) Relative mRNA levels of WFS1 in iPSCs treated with or without P+T for 48 hours (n=5, **P<0.01 by unpaired t-test compared to Ctrl). (FIG. 4E) Representative immunofluorescence images of neural progenitor cell (NPC) markers in NPCs differentiated
from patient-derived iPSCs. Scale bar: 100 µm. (FIG. 4F) qPCR analysis of ER stress related genes in NPCs treated with or without P+T for 48 hours. (n=6, *P<0.05, **P<0.01 and ****P<0.0001 by unpaired t-test compared to Ctrl). (FIG. 4G) Mitochondrial respiration of NPCs treated with or without P+T for 48 hours represented as percentage of baseline oxygen consumption rate (OCR) measurements. Respiration was interrogated by measuring changes in relative OCR after injection with oligomycin (OM), FCCP, and antimycin A (AA)/rotenone (R) (n=3, W024: ***P<0.001, W392: *P<0.05, and W121: *P<0.05 by unpaired t-test compared to Ctrl Area under curve (AUC)). (FIG. 4H) Caspase 3/7 activity normalized by cell viability in NPCs treated with or without either of 4-PBA, TUDCA and P+T for 48 hours. (n=7, ***P<0.001 and ****P<0.0001 by one-way ANOVA compared to Ctrl, #P<0.05, ##P<0.01 and ####P<0.0001 by one-way ANOVA). FIGS. 5A-5C. Comparison of ER stress levels in NPCs among cell lines. (FIG. 5A) Representative immunofluorescence image of neural progenitor cell (NPC) markers in NPCs differentiated from control iPSC line AN1.1. Scale bar: 100 µm. (FIG. 5B) qPCR analysis of WFS1 expression in NPCs differentiated from each iPSC line (AN1.1: n=4, W024 and W392: n=6, W121: n=7. *P<0.05, ***P<0.001 and ****P<0.0001 by one-way ANOVA compared to AN1.1. #P<0.05 and ##P<0.01 by one-way ANOVA). (FIG. 5C) qPCR analysis of ER stress related genes in NPCs differentiated from each iPSC line. (AN1.1: n=4, W024 and W392: n=6, W121: n=7. *P<0.05, ***P<0.001 and ****P<0.0001 by one-way ANOVA compared to AN1.1. #P<0.05 and ##P<0.01 by one-way ANOVA). FIGS. 6A-6B. Comparison of each treatment effect on WFS1 protein and ER stress levels. (FIG. 6A) (Upper) Representative blotting image of WFS1 and α-Tubulin in iPSCs treated with or without 4-PBA, TUDCA or P+T for 48 hours. (Lower) A quantification of WFS1 protein levels normalized with α-Tubulin. (n=3, *P<0.05, **P<0.01 and ****P<0.0001 by one-way ANOVA compared to Ctrl. #P<0.05, ##P<0.01 and ####P<0.0001 by one-way ANOVA). (FIG. 6B) qPCR analysis of ER stress related genes in NPCs treated with or without 4-PBA, TUDCA or P+T. (W024: n=5, W392: n=4, W121: n=5. *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001 by one-way ANOVA compared to Ctrl. #P<0.05 by one-way ANOVA). FIGS. 7A-7C. Comparison of each treatment effect on mitochondrial DNA contents, mitochondrial membrane potentials and apoptosis. (FIG. 7A) Relative mitochondrial DNA (mtDNA) copy numbers normalized to nuclear DNA (nDNA) measured by qPCR analysis in NPCs treated with or without 4-PBA, TUDCA or P+T for 48 hours. (W024: n=3, W392: n=4, W121: n=4. *P<0.05 and **P<0.01 by one-way ANOVA compared to Ctrl. #P<0.05,
##P<0.01 and ###P<0.001 by one-way ANOVA). (FIG. 7B) Mitochondrial membrane potentials measured by fluorescent probe TMRM in NPCs treated with or without 4-PBA, TUDCA or P+T for 48 hours (n=6. ****P<0.0001 by one-way ANOVA compared to Ctrl. ###P<0.001 by one-way ANOVA). (FIG. 7C) (Upper) Representative blotting image of cleaved-Caspase3 and α-Tubulin in NPCs treated with or without 4-PBA, TUDCA or P+T for 48 hours. (Lower) A quantification of cleaved-Caspase3 protein levels normalized with α- Tubulin. (n=3, *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001 by one-way ANOVA compared to Ctrl. #P<0.05 and ##P<0.01 by one-way ANOVA). FIGS. 8A-8B P+T treatment reduced caspase 3/7 activity in NPCs derived from patients with typical Wolfram syndrome. (FIG.8A) Information on the four patients with typical Wolfram syndrome, including the genetic location of autosomal recessive pathogenic variants in WFS1 and the onset age of symptoms. The ages indicate when subjects were included in the study. DM: Diabetes Mellitus, OA: Optic nerve atrophy. (FIG. 8B) Caspase 3/7 activity normalized by cell viability in NPCs treated with or without P+T for 24 hours. (n=6, ****P < 0.0001 by unpaired t-test compared to Ctrl). FIGS. 9A-9I. Insulin secretion is increased by a combination treatment of 4-PBA and TUDCA in SC-islets with WFS1 c.1672C>T, p.R558C variant. (FIG. 9A) Representative flow cytometry dot plots and (FIG. 9B) quantified fraction of cells expressing or co- expressing pancreatic β cell or committed endocrine cell markers for AN1.1 (n=4) W024 (n=3) and W121 (n=3) stage 6 SC-islets (*P<0.05 and ****P<0.0001 by two-way ANOVA compared to AN1.1. #P<0.05, ##P<0.01 and ####P<0.0001 by two-way ANOVA). (FIG. 9C) (Left) Representative blotting image of WFS1 and α-Tubulin in stage 6 SC-islets. (Right) A quantification of relative WFS1 protein level normalized with α-Tubulin (n = 3, **P<0.01 and ***P<0.001 by one-way ANOVA compared to AN1.1. #P<0.05 by one-way ANOVA). (FIG. 9D) Relative mRNA levels of WFS1 in stage 6 SC-islets (n=4, **P<0.01 by one-way ANOVA compared to AN1.1) (FIG. 9E) Static GSIS functional assessment of AN1.1 (n = 7), W024 (n = 6) and W121 (n = 8) stage 6 SC-islets (*P < 0.05 and ***P < 0.001 by two-way ANOVA compared to 2 mM of each line. ##P < 0.01 and ####P < 0.0001 by two-way ANOVA). (FIG. 9F) A schematic of P+T verification in SC-islets. (FIG. 9G) (Upper) Representative blotting images of WFS1 and α-Tubulin in stage 6 SC-islets treated with or without P+T for 7 days. (Lower) A quantification of WFS1 protein levels normalized with α- Tubulin. (n=3, *P<0.05 by unpaired t-test compared to Ctrl). (FIG. 9H) Caspase 3/7 activity normalized by cell viability in stage 6 SC-islets treated with or without P+T for 7 days (n=3, ***P < 0.001 and ****P < 0.0001 by unpaired t-test compared to Ctrl). (FIG. 9I) Static GSIS
functional assessment of W024 (n = 5) and W121 (n = 4) treated with or without P+T for 7 days (*P < 0.05 by one-way paired t-test compared to 2 mM of each condition. #P < 0.05 and ##P < 0.01 by two-way unpaired t-test). CP: C-peptide, CHGA: Chromogranin A. FIG. 10 Electron microscopic (EM) analysis of SC-islets. Representative EM images for AN1.1, W024 and W121 stage 6 SC-islets treated with or without P+T for 7 days. Scale bar, 600 nm. Red arrows indicate dilated endoplasmic reticulum (ER). FIGS. 11A-11B. in vivo verification of a combination treatment with chemical chaperones (FIG. 11A) IP-GTT with WT or Wfs1 KO mice at baseline and 1 month after feeding with either Ctrl or P+T chow. (FIG. 11B) AUCs of the IP-GTT (KO, Ctrl: n=12, KO, P+T: n=12, WT: n=7 **P < 0.01 and ***P < 0.001 by one-way ANOVA, ##P<0.01 and ####P<0.0001 by one-way ANOVA compared to WT: Baseline, ††††P<0.0001 by one-way ANOVA compared to WT: 1 month). FIGS. 12A-12G Additional in vivo verification of a combination treatment with chemical chaperones. (FIG. 12A) Serum insulin levels in WT and Wfs1 KO mice at 5-6 weeks old before feeding with either Ctrl or P+T chow (WT: n=5, KO, Ctrl: n=7, KO, P+T: n=9. *P < 0.05 and **P < 0.01 by two-way ANOVA). (FIG. 12B) Food consumption rate in Wfs1 KO mice fed with either Ctrl or P+T chow. (FIG. 12C) Body weight of Wfs1 KO mice before and after feeding with either Ctrl or P+T chow (KO, Ctrl: n=14, KO, P+T: n=14). (FIG. 12D) IP-ITT with WT or Wfs1 KO mice before (Baseline) and after (1 month) feeding with either Ctrl or P+T chow (WT: n=5, KO, Ctrl: n=5, KO, P+T: n=8. *P<0.05 by two-way ANOVA compared between WT and KO, Ctrl. #P<0.05 and ####P<0.0001 by two-way ANOVA compared between WT and KO, P+T). (FIG.12E) IP-ITT with Wfs1 KO mice fed with either Ctrl or P+T chow comparing between before (Baseline) and after (1 month) the feeding for each group. (FIG. 12F) Serum insulin levels in WT and Wfs1 KO mice fed with either Ctrl or P+T chow for 1 month (WT: n=6, KO, Ctrl: n=7, KO, P+T: n=9. *P<0.05, **P<0.01 and ****P<0.0001 by two-way ANOVA). (FIG. 12G) Serum insulin levels in Wfs1 KO mice fed with either Ctrl or P+T comparing between before (Baseline) and after (1 month) the feeding for each group (*P<0.05 by paired t-test). DETAILED DESCRIPTION Applicant has discovered that a combination of a bile acid (e.g. Taurursodiol (TURSO)) and a phenylbutyrate compound (e.g. sodium phenylbutyrate) can be used for treating one or more symptoms of Wolfram syndrome. The present disclosure provides methods of treating at
least one symptom of Wolfram syndrome in a subject by administering a bile acid (e.g. TURSO) and a phenylbutyrate compound (e.g. sodium phenylbutyrate). The subjects in need of treatment can have or be at risk for developing diabetes, optic nerve atrophy, or a hearing impairment. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. Certain ranges are presented herein with numerical values being preceded by the term “about”. The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. Unless otherwise defined, all terms of art, notations, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this application pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. I. Wolfram syndrome Wolfram syndrome is a rare genetic disorder that can be caused by pathogenic variants in the Wolframin (WFS1) gene or, in a small fraction of patients, pathogenic variants in the CDGSH iron sulfur domain protein 2 (CISD2) gene; and manifested by diabetes insipidus, diabetes mellitus (e.g. juvenile-onset insulin-dependent diabetes), optic nerve atrophy, and progressive neurodegeneration. Many patients also develop other symptoms, ranging from hearing loss and endocrine deficiencies to neurological and psychiatric conditions. Accordingly, recent clinical and genetic findings have revealed that Wolfram syndrome is best
characterized as a spectrum disorder. Wolfram syndrome is a progressive neurodegenerative disorder in which patients can present with nonautoimmune and non-HLA-linked diabetes mellitus followed by optic atrophy in the first decade; cranial diabetes insipidus and sensorineural deafness in the second decade; renal tract abnormalities early in the third decade; and multiple neurological abnormalities, such as cerebellar ataxia, myoclonus, and psychiatric illness early in the fourth decade. Wolfram syndrome patients usually die from central respiratory failure as a result of brainstem atrophy in their third or fourth decade. A large degree of inter-subject variability exists in the rate of progression. The clinical phenotype of Wolfram syndrome can show resemblance with mitochondrial disorders, such as maternally inherited diabetes and deafness, mitochondrial encephalopathy, mitochondrial myopathy, lactic acidosis and stroke-like episodes, or Leber’s hereditary optic neuropathy. WFS1 variants associated with Wolfram syndrome include missense, nonsense, frameshift, in-frame insertion or deletions, and splice-site variants. Variants of WFS1 are known in the art and described in e.g., van ven Ouweland JM, et al. Molecular characterization of WFS1 in patients with Wolfram syndrome. The Journal of molecular diagnostics 2003;5(2):88-95 and Khanim F, et al. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Human mutation. 2001;17(5):357-67. WFS1 encodes an endoplasmic reticulum (ER) transmembrane protein. The ER is a network within all cells involved in protein synthesis, calcium storage and handling, redox regulation, steroid synthesis, and cell signaling, including apoptotic signaling. Given the vital functions of the ER, its dysfunction can trigger a range of cellular pathologies. Studies have shown that pancreatic beta cells and neurons are particularly sensitive to ER dysfunction, potentially due to high rates of hormone and neurotransmitter synthesis, respectively. WFS1 can regulate Ca2+ homeostasis in the ER, which is crucial in the synthesis and secretion of neurotransmitters and hormones such as insulin. WFS1 deficiency in the ER causes Ca2+ homeostasis disruption, leading to chronic ER stress followed by the unfolded protein response (UPR). WFS1 also negatively regulates ATF6, a UPR molecule, inhibiting hyperactivation of ATF6 and consequent cell apoptosis. Furthermore, WFS1 can impact mitochondrial function by transporting Ca2+ from the ER to the mitochondria via the mitochondria-associated ER membrane (MAM). In Wolfram syndrome, pancreatic β cells and neuronal cells can be lost as a consequence of mutations in the WFS1 gene. In cell and animal models of Wolfram syndrome, WFS1 mutations lead to ER stress, pancreatic β cell dysfunction, and the initiation of ER-associated cell death. A small portion of patients have mutations in the WFS2 (CISD2) gene. WFS2 also encodes an ER transmembrane protein. In patients with WFS2 mutations, diabetes mellitus and
hearing impairment are reported. The clinical phenotype of these patients may differ from patients carrying WFS1 mutations with the absence of diabetes insipidus, the presence of upper intestinal ulcers and bleeding events, and defective platelet aggregation. The methods described herein can be used for treating a subject that exhibits one or more symptoms associated with Wolfram syndrome, or has been diagnosed with Wolfram syndrome. In some embodiments, the subject may be suspected as having Wolfram syndrome, and/or at risk for developing Wolfram syndrome. The methods described herein can further include determining that a subject has or is at risk for developing Wolfram syndrome, diagnosing a subject as having or at risk for developing Wolfram syndrome, or selecting a subject having or at risk for developing Wolfram syndrome. A number of features, symptoms, and conditions are associated with Wolfram syndrome and can be used for diagnostic purposes. The subject can have or be at risk for developing diabetes mellitus. For example, the subject can have or be at risk for developing juvenile-onset diabetes mellitus (e.g. with an onset age of < 15 years). The subject can have or be at risk for developing optic atrophy (e.g. onset age < 15 years), high-tone sensorineural hearing impairment (e.g., congenital hearing impairment), cerebellar ataxia, autonomic dysfunction, dementia or intellectual disability, psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction, diabetes insipidus (e.g., central diabetes insipidus), delayed/absent puberty, hypogonadism in males, non-autoimmune hypothyroidism, growth retardation, cardiomyopathy and structural congenital heart defects. Methods of detecting the above conditions are known in the art. For example, the subject can be diagnosed based on clinical history, family history, physical or neurological examinations. A subject may also be identified as having or at risk for developing Wolfram syndrome based on genetic testing. Genetic testing approaches can include gene-targeted testing (single- gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. For example, sequence analysis of one or more genes involved in Wolfram syndrome (e.g. WFS1, WFS2 or other genes known in the art) can be performed to detect mutations. A deafness multigene panel that includes WFS1 and other genes of interest can be performed as described in Tranebjærg et al. (WFS1 Wolfram Syndrome Spectrum Disorder. 2009 Feb 24. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2022.) In some embodiments, genetic testing can be used in combination with clinical diagnosis to confirm Wolfram syndrome diagnosis. Mutations in the WFS1 gene can include the H313Y mutation (Hansen L, Eiberg H, Barrett T, et al. Mutation analysis of the WFS1 gene
in seven Danish Wolfram syndrome families; four new mutations identified. Eur J Hum Genet. 2005;13(12):1275–84), p.Trp314Arg (Bonnycastle LL, Chines PS, Hara T, et al. Autosomal dominant diabetes arising from a wolfram syndrome mutation. Diabetes. 2013;62(11):3943– 50.), the c.1672C>T, p.R558C mutation, and the p.P885L mutation. Other mutations of WFS1 are known in the art. The subject may have shown one or more symptoms of Wolfram syndrome (e.g. any symptoms of Wolfram syndrome described herein or known in the art) for about 1 day to about 5 years (e.g. about 1 to about 6 months, about 7 to about 18 months, or about 2, 3, or 4 years). The subject may have been diagnosed with Wolfram syndrome for about for about 1 day to about 5 years (e.g. about 1 to about 6 months, about 7 to about 18 months, or about 2, 3, or 4 years). The subject can be confirmed or identified, e.g. by a healthcare professional, as having Wolfram syndrome. Multiple parties may be included in the process of diagnosis. For example, where samples are obtained from a subject as part of a diagnosis, a first party can obtain a sample from a subject and a second party can test the sample. In some embodiments, the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner). Skilled practitioners will appreciate that certain factors can affect the bioavailability and metabolism of the administered compounds for a subject, and can make adjustments accordingly. These include but are not limited to liver function (e.g. levels of liver enzymes), renal function, and gallbladder function (e.g., ion absorption and secretion, levels of cholesterol transport proteins). There can be variability in the levels of exposure each subject has for the administered compounds (e.g., bile acid and a phenylbutyrate compound), differences in the levels of excretion, and in the pharmacokinetics of the compounds in the subjects being treated. Any of the factors described herein may affect drug exposure by the subject. For instance, decreased clearance of the compounds can result in increased drug exposure, while improved renal function can reduce the actual drug exposure. The extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment. The methods described herein can be used for preventative and prophylaxis purposes. II. Composition The present disclosure provides methods of treating at least one symptom of Wolfram syndrome in a subject, the methods including administering to the subject a bile acid or a pharmaceutically acceptable salt thereof and a phenylbutyrate compound. In some
embodiments, the methods include administering a composition comprising a TURSO and a sodium phenylbutyrate to a subject. Bile Acid As used herein, “bile acid” refers to naturally occurring surfactants having a nucleus derived from cholanic acid substituted with a 3α-hydroxyl group and optionally with other hydroxyl groups as well, typically at the C6, C7 or C12 position of the sterol nucleus. Bile acid derivatives (e.g., aqueous soluble bile acid derivatives) and bile acids conjugated with an amine are also encompassed by the term “bile acid”. Bile acid derivatives include, but are not limited to, derivatives formed at the carbon atoms to which hydroxyl and carboxylic acid groups of the bile acid are attached with other functional groups, including but not limited to halogens and amino groups. Soluble bile acids may include an aqueous preparation of a free acid form of bile acids combined with one of HCl, phosphoric acid, citric acid, acetic acid, ammonia, or arginine. Suitable bile acids include but are not limited to, taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also referred to as “chenodiol” or “chenic acid”), cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, or an analog, derivative, or prodrug thereof. In some embodiments, the bile acids of the present disclosure are hydrophilic bile acids. Hydrophilic bile acids include but are not limited to, TURSO, UDCA, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid. Pharmaceutically acceptable salts or solvates of any of the bile acids disclosed herein are also contemplated. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the bile acids of the present disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2- hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. The terms “tauroursodeoxycholic acid” (TUDCA) and “taurursodiol” (TURSO) are
used interchangeably herein. The bile acid described herein can be TURSO, as shown in formula I (with labeled carbons to assist in understanding where substitutions may be made). In some embodiments, the TURSO is a hydrate, such as TURSO dihydrate.
. The bile acid described herein can be UDCA as shown in formula II (with labeled carbons to assist in understanding where substitutions may be made).
, or a pharmaceutically acceptable salt thereof. Derivatives of bile acids of the present disclosure can be physiologically related bile acid derivatives. For example, any combination of substitutions of hydrogen at position 3 or 7, a shift in the stereochemistry of the hydroxyl group at positions 3 or 7, in the formula of TURSO or UDCA are suitable for use in the present composition. The “bile acid” can also be a bile acid conjugated with an amino acid. The amino acid in the conjugate can be, but are not limited to, taurine, glycine, glutamine, asparagine, methionine, or carbocysteine. Other amino acids that can be conjugated with a bile acid of the present disclosure include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, cysteine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan, as well as β-alanine, and γ-aminobutyric acid. One example of such a bile acid is a compound of formula III:
III, wherein R is -H or C1-C4 alkyl; R1 is -CH2-SO3R3, CH2COOH, or CH2CH2COOH, and R2 is -H; or R1 is -COOH and R2 is -CH2-CH2-CONH2, -CH2-CONH2, -CH2-CH2-SCH3, CH2CH2CH2NH(C=NH)NH2, CH2(imidazolyl), CH2CH2CH2CH2NH2, CH2COOH, CH2CH2COOH, CH2OH, CH(OH)CH3, CH2SH, pyrrolidin-2-yl, CH3, 2-propyl, 2-butyl, 2- methylbutyl, CH2(phenyl), CH2(4-OH-phenyl), or -CH2-S-CH2-COOH; and R3 is -H or the residue of an amino acid, or a pharmaceutically acceptable analog, derivative, prodrug thereof, or a mixture thereof. One example of the amino acid is a basic amino acid. Other examples of the amino acid include glycine, glutamine, asparagine, methionine, carbocysteine, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, cysteine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan, as well as β-alanine, and γ-aminobutyric acid. Another example of a bile acid of the present disclosure is a compound of formula IV:
wherein R is -H or C1-C4 alkyl; R1 is -CH2-SO3R3, and R2 is -H; or R1 is -COOH and R2 is -CH2-CH2-CONH2, -CH2-CONH2, -CH2-CH2-SCH3, or - CH2-S-CH2-COOH; and R3 is -H or the residue of a basic amino acid, or a pharmaceutically acceptable analog,
derivative, prodrug thereof, or a mixture thereof. Examples of basic amino acids include lysine, histidine, and arginine. In some embodiments, the bile acid is TURSO. TURSO is an ambiphilic bile acid and is the taurine conjugate form of UDCA. TURSO recovers mitochondrial bioenergetic deficits through incorporating into the mitochondrial membrane, reducing Bax translocation to the mitochondrial membrane, reducing mitochondrial permeability, and increasing the apoptotic threshold of the cell (Rodrigues et al. Biochemistry 42, 10: 3070-3080, 2003). It is used for the treatment of cholesterol gallstones, where long periods of treatment is generally required (e.g., 1 to 2 years) to obtain complete dissolution. It has been used for the treatment of cholestatic liver diseases including primary cirrhosis, pediatric familial intrahepatic cholestasis and primary sclerosing cholangitis and cholestasis due to cystic fibrosis. TURSO is contraindicated in subjects with biliary tract infections, frequent biliary colic, or in subjects who have trouble absorbing bile acids (e.g. ileal disease or resection). Drug interactions may include with substances that inhibit the absorption of bile acids, such as cholestyramine, and with drugs that increase the elimination of cholesterol in the bile (TURSO reduces biliary cholesterol content). Based on similar physicochemical characteristics, similarities in drug toxicity and interactions exist between TURSO and UDCA. The most common adverse reactions reported with the use of TURSO (≥1%) are: abdominal discomfort, abdominal pain, diarrhea, nausea, pruritus, and rash. There are some cases of pruritus and a limited number of cases of elevated liver enzymes. In some embodiments, the bile acid is UDCA. UDCA, or ursodiol, has been used for treating gallstones, and is produced and secreted endogenously by the liver as a taurine (TURSO) or glycine (GUDCA) conjugate. Taurine conjugation increases the solubility of UDCA by making it more hydrophilic. TURSO is taken up in the distal ileum under active transport and therefore likely has a slightly a longer dwell time within the intestine than UDCA which is taken up more proximally in the ileum. Ursodiol therapy has not been associated with liver damage. Abnormalities in liver enzymes have not been associated with Actigall® (Ursodiol USP capsules) therapy and, Actigall® has been shown to decrease liver enzyme levels in liver disease. However, subjects given Actigall® should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances. Previous studies have shown that bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase
hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol. Phenylbutyrate compounds Phenylbutyrate compound is defined herein as encompassing phenylbutyrate (a low molecular weight aromatic carboxylic acid) as a free acid (4-phenylbutyrate (4-PBA), 4- phenylbutyric acid, or phenylbutyric acid), and pharmaceutically acceptable salts, co-crystals, polymorphs, hydrates, solvates, conjugates, derivatives or pro-drugs thereof. Phenylbutyrate compounds described herein also encompass analogs of 4-PBA, including but not limited to Glyceryl Tri-(4-phenylbutyrate), phenylacetic acid (which is the active metabolite of PBA), 2- (4-Methoxyphenoxy) acetic acid (2-POAA-OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA- NO2), and 2-(2-Naphthyloxy) acetic acid (2-NOAA), and their pharmaceutically acceptable salts. Phenylbutyrate compounds also encompass physiologically related 4-PBA species, such as but not limited to any substitutions for Hydrogens with Deuterium in the structure of 4-PBA. Other HDAC2 inhibitors are contemplated herein as substitutes for phenylbutyrate compounds. Physiologically acceptable salts of phenylbutyrate, include, for example sodium, potassium, magnesium or calcium salts. Other example of salts include ammonium, zinc, or lithium salts, or salts of phenylbutyrate with an orgain amine, such as lysine or arginine. In some embodiments of any of the methods described herein, the phenylbutyrate compound is sodium phenylbutyrate. Sodium phenylbutyrate has the following formula:
Phenylbutyrate is a pan-HDAC inhibitor and can ameliorate ER stress through upregulation of the master chaperone regulator DJ-1 and through recruitment of other chaperone proteins (See e.g., Zhou et al. J Biol Chem. 286: 14941-14951, 2011 and Suaud et al. JBC. 286:21239-21253, 2011). The large increase in chaperone production reduces activation of canonical ER stress pathways, folds misfolded proteins, and has been shown to increase survival in in vivo models including the G93A SOD1 mouse model of ALS (See e.g., Ryu, H et al. J Neurochem. 93:1087-1098, 2005). Formulation Bile acids and phenylbutyrate compounds described herein can be formulated for use
as or in pharmaceutical compositions. For example, the methods described herein can include administering an effective amount of a composition comprising TURSO and sodium phenylbutyrate. The term “effective amount”, as used herein, refer to an amount or a concentration of one or more drugs administered for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome. The composition can include about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO and about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate. In some embodiments, the composition includes about 9.7% w/w of TURSO and 29.2% w/w of sodium phenylbutyrate. The sodium phenylbutyrate and TURSO can be present in the composition at a ratio by weight of between about 1:1 to about 4:1 (e.g., about 2:1 or about 3:1). In some embodiments, the ratio between sodium phenylbutyrate and TURSO is about 3:1. The compositions described herein can include any pharmaceutically acceptable carrier, adjuvant, and/or vehicle. The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound disclosed herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The pharmaceutical compositions may contain any conventional non-toxic pharmaceutically- acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. Compositions of the present disclosure can include about 8% to about 24% w/w of dextrates (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6% w/w of dextrates). Both anhydrous and hydrated dextrates are contemplated herein. The dextrates of the present disclosure can include a mixture of saccharides developed from controlled enzymatic hydrolysis of starch. Some embodiments of any of the compositions described
herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra). Compositions of the present disclosure can include about 1% to about 6% w/w of sugar alcohol (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w of sugar alcohol). Sugar alcohols can be derived from sugars and contain one hydroxyl group (-OH) attached to each carbon atom. Both disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols can be natural or produced by hydrogenation of sugars. Exemplary sugar alcohols include but are not limited to, sorbitol, xylitol, and mannitol. In some embodiments, the composition comprises about 1% to about 6% w/w (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w) of sorbitol. Compositions of the present disclosure can include about 22% to about 35% w/w of maltodextrin (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w/w, e.g., about 28.3% w/w of maltodextrin). Maltodextrin can form a flexible helix enabling the entrapment of the active ingredients (e.g., any of the phenylbutyrate compounds and bile acids described herein) when solubilized into solution, thereby masking the taste of the active ingredients. Maltodextrin produced from any suitable sources are contemplated herein, including but not limited to, pea, rice, tapioca, corn, and potato. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition includes about 28.3% w/w of pea maltodextrin. For example, pea maltodextrin obtained from Roquette (KLEPTOSE® LINECAPS) can be used. The compositions described herein can further include sugar substitutes (e.g. sucralose). For example, the compositions can include about 0.5% to about 5% w/w of sucralose (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w/w of sucralose). Other sugar substitutes contemplated herein include but are not limited to aspartame, neotame, acesulfame potassium, saccharin, and advantame. In some embodiments, the compositions include one or more flavorants. The compositions can include about 2% to about 15% w/w of flavorants (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w). Flavorants can include substances that give another substance flavor, or alter the characteristics of a composition by affecting its taste. Flavorants can be used to mask unpleasant tastes without affecting physical and chemical stability, and can be selected based on the taste of the drug to be incorporated. Suitable flavorants include but are not limited to natural flavoring substances, artificial flavoring substances, and imitation flavors. Blends of flavorants can also be used. For example, the compositions described herein can include two
or more (e.g., two, three, four, five or more) flavorants. Flavorants can be soluble and stable in water. Selection of suitable flavorants can be based on taste testing. For example, multiple different flavorants can be added to a composition separately, which are subjected to taste testing. Exemplary flavorants include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry or mixed berry flavor powder). The compositions described herein can include about 0.5% to about 1.5% w/w (e.g., about 1% w/w) of a mixed berry flavor powder and/or about 5% to about 7% w/w (e.g., about 6.3% w/w) of a masking flavor. Suitable masking flavors can be obtained from e.g., Firmenich. The compositions described herein can further include silicon dioxide (or silica). Addition of silica to the composition can prevent or reduce agglomeration of the components of the composition. Silica can serve as an anti-caking agent, adsorbent, disintegrant, or glidant. In some embodiments, the compositions described herein include about 0.1% to about 2% w/w of porous silica (e.g., about 0.3% to about 1.5%, about 0.5% to about 1.2%, or about 0.8% to about 1%, e.g., 0.9% w/w). Porous silica may have a higher H2O absorption capacity and/or a higher porosity as compared to fumed silica, at a relative humidity of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher). The porous silica can have an H2O absorption capacity of about 5% to about 40% (e.g. about 20% to about 40%, or about 30% to about 40%) by weight at a relative humidity of about 50%. The porous silica can have a higher porosity at a relative humidity of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher) as compared to that of fumed silica. In some embodiments, the porous silica have an average particle size of about 2 µm to about 10 µm (e.g. about 3 µm to about 9 µm, about 4 µm to about 8 µm, about 5 µm to about 8 µm, or about 7.5 µm). In some embodiments, the porous silica have an average pore volume of about 0.1 cc/gm to about 2.0 cc/gm (e.g., about 0.1 cc/gm to about 1.5 cc/gm, about 0.1 cc/gm to about 1 cc/gm, about 0.2 cc/gm to about 0.8 cc/gm, about 0.3 cc/gm to about 0.6 cc/gm, or about 0.4 cc/gm). In some embodiments, the porous silica have a bulk density of about 50 g/L to about 700 g/L (e.g. about 100 g/L to about 600 g/L, about 200 g/L to about 600 g/L, about 400 g/L to about 600 g/L, about 500 g/L to about 600 g/L, about 540 g/L to about 580 g/L, or about 560 g/L). In some embodiments, the compositions described herein include about 0.05% to about 2% w/w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace). The compositions described herein can further include one or more buffering agents. For example, the compositions can include about 0.5% to about 5% w/w of buffering agents (e.g., about 1% to about 4% w/w, about 1.5% to about 3.5% w/w, or about 2% to about 3%
w/w, e.g. about 2.7% w/w of buffering agents). Buffering agents can include weak acid or base that maintain the acidity or pH of a composition near a chosen value after addition of another acid or base. Suitable buffering agents are known in the art. In some embodiments, the buffering agent in the composition provided herein is a phosphate, such as a sodium phosphate (e.g., sodium phosphate dibasic anhydrous). For example, the composition can include about 2.7% w/w of sodium phosphate dibasic. The compositions can also include one or more lubricants. For example, the compositions can include about 0.05% to about 1% w/w of lubricants (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8 %, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g. about 0.5% w/w of lubricants). Exemplary lubricants include, but are not limited to sodium stearyl fumarate, magnesium stearate, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, polyethylene glycols, alkyl sulphates, glyceryl behenate, and hydrogenated oil. Additional lubricants are known in the art. In some embodiments, the composition includes about 0.05% to about 1% w/w (e.g., any of the subranges of this range described herein) of sodium stearyl fumarate. For example, the composition can include about 0.5% w/w of sodium stearyl fumarate. In some embodiments, the composition include about 29.2% w/w of sodium phenylbutyrate, about 9.7% w/w of TURSO, about 15.6% w/w of dextrates, about 3.9% w/w of sorbitol, about 1.9% w/w of sucralose, about 28.3% w/w of maltodextrin, about 7.3% w/w of flavorants, about 0.9% w/w of silicon dioxide, about 2.7% w/w of sodium phosphate (e.g. sodium phosphate dibasic), and about 0.5% w/w of sodium stearyl fumerate. The composition can include about 3000 mg of sodium phenylbutyrate, about 1000 mg of TURSO, about 1600 mg of dextrates, about 400 mg of sorbitol, about 200 mg of sucralose, about 97.2 mg of silicon dioxide, about 2916 mg of maltodextrin, about 746 mg of flavorants (e.g. about 102 mg of mixed berry flavor and about 644 mg of masking flavor), about 280 mg of sodium phosphate (e.g. sodium phosphate dibasic), and about 48.6 mg of sodium stearyl fumerate. Additional suitable sweeteners or taste masking agents can also be included in the compositions, such as but not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solid. Water soluble artificial sweeteners are contemplated herein, such as the soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamate salts, acesulfam potassium (acesulfame K), and the free acid form of saccharin and aspartame based sweeteners such as L-aspartyl- phenylalanine methyl ester, Alitame® or Neotame®. The amount of sweetener or taste
masking agents can vary with the desired amount of sweeteners or taste masking agents selected for a particular final composition. Pharmaceutically acceptable binders in addition to those described above are also contemplated. Examples include cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g. Primogel® and Explotab®). Additional fillers, diluents or binders may be incorporated such as polyols, sucrose, sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g., spray-dried lactose, α-lactose, β- lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floc®), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka- Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g. L-HPC- CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex® 5 and Lodex® 10), starches or modified starches (including potato starch, maize starch and rice starch), sodium chloride, sodium phosphate, calcium sulfate, and calcium carbonate. The compositions described herein can be formulated or adapted for administration to a subject via any route (e.g. any route approved by the Food and Drug Administration (FDA)). Exemplary methods are described in the FDA's CDER Data Standards Manual, version number 004 (which is available at fda.give/cder/dsm/DRG/drg00301.html). Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (subcutaneous, intracutaneous, intravenous, intradermal, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation or through a feeding tube), transdermal (topical), transmucosal, and rectal administration. Pharmaceutical compositions can be in the form of a solution or powder for inhalation and/or nasal administration. In some embodiments, the pharmaceutical composition is formulated as a powder filled sachet. Suitable powders may include those that are substantially soluble in water. Pharmaceutical compositions may be formulated according to techniques
known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The compositions can be orally administered in any orally acceptable dosage form including, but not limited to, powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of powders for oral administration, the powders can be substantially dissolved in water prior to administration. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, may be added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Alternatively or in addition, the compositions can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. In some embodiments, therapeutic compositions disclosed herein can be formulated for sale in the US, imported into the US, and/or exported from the US. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for
administration. In some embodiments, the invention provides kits that include the bile acid and phenylbutyrate compounds. The kit may also include instructions for the physician and/or patient, syringes, needles, box, bottles, vials, etc. III. Methods of treatment The present disclosure provides methods of treating one or more symptoms of Wolfram syndrome in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a combination of a bile acid compound or a pharmaceutically acceptable salt there of (e.g. TURSO) and a phenylbutyrate compound (e.g. sodium phenylbutyrate). The bile acid or a pharmaceutically acceptable salt thereof and the phenylbutyrate compound can be administered separately or concurrently, including as a part of a regimen of treatment. The compounds can be administered daily (e.g. once a day, twice a day, or three times a day or more), weekly, monthly, or quarterly. The compounds can be administered over a period of weeks, months, or years. For example, the compounds can be administered over a period of at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more. The compounds can be administered once a day or twice a day for 60 days or less (e.g., 55 days, 50 days, 45 days, 40 days, 35 days, 30 days or less). Alternatively, the bile acid and phenylbutyrate compound can be administered once a day or twice a day for more than 60 days (e.g., more than 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 180, 200, 250, 300, 400, 500, 600 days). TURSO can be administered at an amount of about 0.5 to about 5 grams per day (e.g., about 0.5 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 0.5 to about 3, about 0.5 to about 2.5, about 0.5 to about 2, about 0.5 to about 1.5, about 0.5 to about 1, about 1 to about 5, about 1 to about 4.5, about 1 to about 4, about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 5, about 1.5 to about 4.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 5, about 2 to about 4.5, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 5, about 2.5 to about 4.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 5, about 3 to about 4.5, about 3 to about 4, about 3 to about 3.5, about 3.5 to about 5 about 3.5 to about 4.5, about 3.5 to about 4, about 4 to about 5, about 4 to about 4.5, or about 4.5 to about 5 grams). In some embodiments, TURSO is administered at an amount of about 1 to about 2 grams per
day (e.g., about 1 to about 1.8 grams, about 1 to about 1.6 grams, about 1 to about 1.4 grams, about 1 to about 1.2 grams, about 1.2 to about 2.0 grams, about 1.2 to about 1.8 grams, about 1.2 to about 1.6 grams, about 1.2 to about 1.4 grams, about 1.4 to about 2.0 grams, about 1.4 to about 1.8 grams, about 1.4 to about 1.6 grams, about 1.6 to about 2.0 grams, about 1.6 to about 1.8 grams, about 1.8 to about 2.0 grams). In some embodiments, TURSO is administered at an amount of about 1 gram per day. For example, TURSO can be administered at an amount of about 1 gram once a day. In some embodiments, TURSO is administered at an amount of about 2 grams per day. For example, TURSO can be administered at an amount of about 1 gram twice a day. Sodium phenylbutyrate can be administered at an amount of about 0.5 to about 10 grams per day (e.g., about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2.5 to about 9.5, about 2.5 to about 8.5, about 2.5 to about 7.5, about 2.5 to about 6.5, about 2.5 to about 5.5, about 2.5 to about 4.5, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6.5, about 3 to about 6, about 3 to about 5, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 7 to about 10, about 7 to about 9, about 8 to about 10 grams per day). In some embodiments, sodium phenylbutyrate is administered at an amount of about 3 to about 6 grams per day (e.g., about 3 to about 5.5 grams, about 3 to about 5.0 grams, about 3 to about 4.5 grams, about 3 to about 4.0 grams, about 3 to about 3.5 grams, about 3.5 to about 6 grams, about 3.5 to about 5.5 grams, about 3.5 to about 5.0 grams, about 3.5 to about 4.5 grams, about 3.5 to about 4.0 grams, about 4.0 to about 6 grams, about 4.0 to about 5.5 grams, about 4.0 to about 5.0 grams, about 4.0 to about 4.5 grams, about 4.5 to about 6 grams, about 4.5 to about 5.5 grams, about 4.5 to about 5.0 grams, about 5.0 to about 6 grams, about 5.0 to about 5.5 grams, or about 5.5 to about 6.0 grams). In some embodiments, sodium phenylbutyrate is administered at an amount of about 3 grams per day. For example, sodium phenylbutyrate can be administered at an amount of about 3 grams once a day. In some embodiments, sodium phenylbutyrate is administered at an amount of about 6 grams per day. For example, sodium phenylbutyrate can be administered at an amount of about 3 grams twice a day. In some embodiments, the bile acid and phenylbutyrate compound are administered at a ratio by weight of about 2.5:1 to about 3.5:1 (e.g., about 3:1).
The methods described herein can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day, or about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day. The methods can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day for at least about 14 days (e.g., at least about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 30, 35, or 40 days), followed by administering about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day for at least a day (e.g. at least 30, 40, 50, 60, 80, 100, 120, 150, 180, 250, 300, or 400 days). For example, the methods can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day for about 14-21 days, followed by administering about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the methods described herein include administering to a subject about 5 mg/kg to about 100 mg/kg of body weight of TURSO (e.g. about 10 to about 50, about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 75, about 75 to about 80, about 80 to about 85, about 85 to about 90, about 90 to about 95, or about 95 to about 100 mg/kg). In some embodiments, the methods described herein include administering to a subject about 10 mg/kg to about 400 mg/kg of body weight of sodium phenylbutyrate (e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300 to about 400 mg/kg). In some embodiments, TURSO is administered in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of body weight. In some embodiments, sodium phenylbutyrate is administered in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or 150 mg/kg of body weight. The methods described herein can be used for treating or ameliorating at least one symptom of Wolfram syndrome. The methods can also be used for prophylactically treating a subject at risk for developing Wolfram syndrome. The methods can be used to treat subjects who display one or more conditions including, e.g., diabetes insipidus, diabetes mellitus (e.g. juvenile-onset diabetes), optic nerve atrophy, progressive neurodegeneration, hearing loss,
endocrine deficiencies and neurological and psychiatric conditions, cerebellar ataxia, autonomic dysfunction, dementia or intellectual disability, psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction, delayed/absent puberty, hypogonadism in males, non-autoimmune hypothyroidism, growth retardation, cardiomyopathy or structural congenital heart defects. In some embodiments, the subject has or is at risk for developing diabetes, for example, insulin-dependent diabetes or juvenile onset diabetes. In some embodiments, the subject has or is at risk for developing optic nerve atrophy or a hearing impairment. In some embodiments, the subject has one or more mutations in the WFS1 gene. For example, the subject may have the c.1672C>T, p.R558C mutation in the WFS1 gene or the c.2654C>T, p.P885L mutation in the WFS1 gene. In some embodiments, the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene. In some embodiments, administration of the combination of the bile acid compound (e.g. TURSO) and the phenylbutyrate compound (e.g. sodium phenylbutyrate) results in improved treatment of one or more symptoms of Wolfram syndrome as compared to each compound alone. For example, treatment with a combination of TURSO and sodium phenylbutyrate can lead to symptom reduction for the subjects described herein to a greater extent or at a faster rate than each compound alone. Methods described in the present disclosure can include treatment of Wolfram syndrome per se, as well as treatment for one or more symptoms of Wolfram syndrome. “Treating” Wolfram syndrome does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity of symptoms or features of the disease is contemplated. “Treating” Wolfram syndrome also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease. “Treating” Wolfram syndrome also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating Wolfram syndrome disclosed herein or known in the art). “Treating” Wolfram syndrome also refers to eliminating or reducing one or more direct or indirect effects of Wolfram syndrome disease progression. The subject may not exhibit signs of Wolfram syndrome but may be at risk for Wolfram syndrome. For instance, the subject may carry mutations in genes associated with Wolfram syndrome, have family history of having Wolfram syndrome. The subject may exhibit early signs of the disease or display symptoms of established or progressive disease. The disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression
of any one or more disease symptoms. The treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing Wolfram syndrome), at symptom onset or immediately following detection of Wolfram syndrome symptoms, upon observation of any one or more symptoms that would lead a skilled practitioner to suspect that the subject may be developing Wolfram syndrome. Treatment can also be initiated at later stages. For example, treatment may be initiated at progressive stages of the disease. Treatment methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of Wolfram syndrome, or at least one symptom of Wolfram syndrome. The duration of prophylaxis treatment can be a single dosage or the treatment may continue (e.g., multiple dosages), e.g., for years or indefinitely for the lifespan of the subject. For example, a subject at risk for Wolfram syndrome may be treated with the methods provided herein for days, weeks, months, or even years so as to prevent the disease from occurring or fulminating. In some embodiments treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment. The treatment provided herein can be administered one or more times daily, or it can be administered weekly or monthly. In some embodiments, treatment can continue until a decrease in the level of disease in the subject is detected. The terms “administer”, “administering”, or “administration” as used herein refers to administering drugs described herein to a subject using any art-known method, e.g., ingesting, injecting, implanting, absorbing, or inhaling, the drug, regardless of form. In some embodiments, one or more of the compounds disclosed herein can be administered to a subject by ingestion orally and/or topically (e.g., nasally). For example, the methods herein include administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician. Following administration of the bile acid or a pharmaceutically acceptable salt thereof and the phenylbutyrate compound, the subject can be evaluated to detect, assess, or determine their level of Wolfram syndrome disease. In some embodiments, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.
Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. The methods described herein can further include administering to the subject one or more additional therapeutic agents, e.g. in amounts effective for treating or achieving a modulation of at least one symptom of Wolfram syndrome. Any Wolfram syndrome therapeutic agents known in the art can be used as an additional therapeutic agent. Exemplary therapeutic agents include valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, and ER Ca2+ stabilizer. The bile acid or a pharmaceutically acceptable salt thereof and the phenylbutyrate compound can be administered shortly after a meal (e.g., within two hours of a meal) or under fasting conditions. The subject may have consumed food items (e.g., solid foods or liquid foods) less than 2 hours before administration of a bile acid or a pharmaceutically acceptable salt thereof and/or a phenylbutyrate compound; or will consume food items less than 2 hours after administration of one or both of the compounds. Food items may affect the rate and extent of absorption of the bile acid or a pharmaceutically acceptable salt thereof and/or the phenylbutyrate compound. For instance, food can change the bioavailability of the compounds by delaying gastric emptying, stimulating bile flow, changing gastrointestinal pH, increasing splanchnic blood flow, changing luminal metabolism of the substance, or physically or chemically interacting with a dosage form or the substance. The nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiological changes in the GI tract in a way that affects drug transit time, luminal dissolution, drug permeability, and systemic availability. In general, meals that are high in total calories and fat content are more likely to affect the GI physiology and thereby result in a larger effect on the bioavailability of a drug. The methods provided herein can further include administering to the subject a plurality of food items, for example, less than 2 hours (e.g., less than 1.5 hour, 1 hour, or 0.5 hour) before or after administering the bile acid or a pharmaceutically acceptable salt thereof, and/or the phenylbutyrate compound.
EXAMPLES Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not in any way intended to limit the scope of this disclosure or the claims. Examples Example 1. Multidimensional analysis and therapeutic development using patient iPSC- derived disease models of Wolfram syndrome To generate induced pluripotent stem cell lines (iPSCs), peripheral blood mononuclear cells (PBMCs) were obtained from patients with Wolfram syndrome. For the in vivo study, 129S6 whole body Wfs1-knockout mice were treated at 5-6 weeks old with control food or food containing AMX0035 (PB: 0.338% and TURSO: 0.225%, refer to AMX0035 chow) for one month. Summary Cellular Function in Neural Progenitor Cells An in vitro assessment was performed to assess whether AMX0035 stabilized WFS1 protein using the HiBiT tagged reporters and if AMX0035 would restore organelle functions in NPCs derived from three patient iPSC lines. The incubation with AMX0035 significantly increased the steady-state levels of WFS1 p.R558C protein. AMX0035 treatment significantly increased WFS1 protein levels in iPSCs derived from all three patient lines assessed. mRNA levels were also increased by the AMX0035 treatment. The expression of ER stress marker genes, BiP and spliced XBP1 (sXBP1), were not affected by AMX0035, whereas ER stress- induced apoptosis genes, CHOP and TXNIP, were significantly decreased in each of the three patient lines. Increased oxygen consumption rates (OCRs) were observed throughout the assay in each of the three patient lines with AMX0035. Moreover, AMX0035 inhibited apoptosis, as indicated by caspase 3/7 activity, in each of the three patient lines. Insulin Secretion and Survival in SC-β cells with WFS1 c.1672C>T, p.R558C variant An in vitro assessment was performed to determine if AMX0035 is effective in ameliorating W024 and W121 SC-islet dysfunction. WFS1 protein expression was restored in the treated SC-islets, as observed in both the W024 and W121 iPSCs. AMX0035 greatly inhibited cell death in the W024 and W121 SC-islets. Mitigation of Cellular Stress in SC-islets with WFS1 c.1672C>T, p.R558C variant An in vitro assessment was performed to assess whether AMX0035 mitigates cellular stress. Gene sets pertaining to apoptosis and ER stress were enriched in the untreated SC-β cells. Gene sets related to insulin secretion, and β cell development were enriched in the AMX0035-treated SC-β cell population. Additionally, gene sets related to regulation of cytosolic K+ and Ca2+ levels were increased, which play an important role in β cell differentiation and function. Progression of the Diabetic Phenotype in Wfs1 Deficient Mice
A mouse model, using 129S6 whole body Wfs1-KO mice, which develops progressive glucose intolerance during adolescence was used to determine the effects of AMX0035 for the Wolfram diabetic phenotype in vivo. After feeding for one month, Wfs1 KO mice fed with control chow developed more severe glucose intolerance. Conversely, an intraperitoneal glucose tolerance test (IP-GTT) blood glucose curve was similar to the baseline outcome in Wfs1 KO mice fed with AMX0035 chow, indicating that AMX0035 chow delayed the progression of the diabetic phenotype. This study harnesses multiple iPSC-derived in vitro disease models and demonstrates effectiveness of AMX0035 in vivo. AMX0035 increased WFS1 expression and inhibited apoptosis by mitigating ER stress and mitochondrial dysfunction. AMX0035 restored WFS1 expression and increased insulin secretion capabilities of W024 and W121 SC-islets. AMX0035 treatment mitigated cellular stress increased by pathogenic WFS1 variants without changing β cell identity, which resulted in increased β cell and insulin secretion in W024 and W121 SC-β cells. In vivo, delays in the Wolfram diabetic phenotype in Wfs1 KO mice when using the AMX0035 chow were observed. Results Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell (iPSC)-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulate genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function by a combination treatment of chemical chaperones mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increases insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. WFS1 c.1672C>T, p.R558C is enriched in Ashkenazi Jewish population and causes a mild form of Wolfram phenotypes To determine the carrier frequency for WFS1 c.1672C>T, p.R558C variant in the Jewish population, we genotyped 87,093 subjects from several Jewish populations. In the original dataset, each subject was classified by self-identification as Ashkenazi, Sephardi, Ashkenazi/Sephardi, Convert, and Unknown. Samples from Converts and Unknown origin made up a total of 773 and were excluded from analysis. The observed frequency of WFS1 c.1672C>T, p.R558C carriers in Ashkenazi Jewish subjects reached 2.32% (1:43), 1.32%
(1:76) for the Ashkenazi/Sephardi, and 0.04% (1:2,268) in Sephardi Jewish subjects (FIG. 1A). To elucidate if WFS1 c.1672C>T, p.R558C was present at higher rates in the Jewish population residing from various countries, we classified data based on self-reported ancestry of four grandparents. Subjects who stated two or more countries of mixed origin were removed from analysis. In cases where South Africa was provided as the country of origin, the samples were redefined as Lithuanian, as South African Jews are primarily of Lithuanian origin. Subjects who had Israel or USA stated in their ancestry were also removed because the Jewish people residing in these countries often have mixed Ashkenazi origins. Subjects that did not provide any information on grandparental origin or stated Unknown were removed. Subjects with Ukrainian origin were merged into the Russian group. Subjects with Belarus and Czechia origin were removed from analysis because they totaled less than 100 subjects and a small sample group can produce spurious signals. In data classified by the country of origin, the frequencies occur as follows: Romania 3.50% (1:29), Poland 2.57% (1:39), Russia 2.07% (1:48), Hungary 1.63% (1:61), Germany 1.60% (1:63) and Lithuania 0.87% (1:116) (FIG. 1B). Clinical investigation revealed that most subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant developed diabetes mellitus, however, the age at diagnosis was greater than that of typical Wolfram syndrome (approximately 6 years) (Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J Med Genet. 1997;34(10):838- 41.) (Table 1). Only four subjects were clinically diagnosed with optic nerve atrophy. Their optic nerve atrophy was mild, and no case was diagnosed legally blind (Table 1). Additionally, no subject developed hearing loss nor diabetes insipidus (Table 1). Together, WFS1 c.1672C>T, p.R558C variant was enriched in the Ashkenazi Jewish population, especially those originated from Romania, and the variant leads to mild or less severe phenotypes of Wolfram syndrome.
The WFS1 p.R558C variant is degraded more than wild-type, but less than WFS1 p.P885L variant Pathogenic WFS1 variants are classified based on their effect on WFS1 expression: class A, depleted WFS1 protein or reduced, defective WFS1 protein, which leads to loss-of- function or incomplete function; class B, expression of defective WFS1 protein leading to gain-of-function. Class A is furthermore divided into three subclasses: class A1, WFS1 depletion due to WFS1 mRNA degradation (nonsense mediated decay, NMD); class A2, WFS1 depletion due to WFS1 protein degradation; class A3, WFS1 depletion due to mRNA and protein degradation (de Heredia ML, et al. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013;15(7):497-506; Rigoli L, et al. Genetic and clinical aspects of
Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr Res. 2018;83(5):921-9.) (FIG. 2). To determine the class specification of the WFS1 c.1672C>T, p.R558C variant, we investigated the thermal stability of WFS1 p.R558C and p.P885L by appending a HiBiT- based tag to detect the variant in cells. The p.R558C variant showed less thermal stability than wild-type WFS1, suggesting an altered folding state, but more stability compared to the known autosomal recessive variant p.P885L which is pathogenic and is associated with a typical form of Wolfram syndrome (Hardy C, et al. Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. American journal of human genetics. 1999;65(5):1279-90.; Qian X, et al. Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. Scientific reports. 2015;5:14731.) (FIG. 3A and B). Both p.R558C and p.P885L expression could be rescued by incubating cells at reduced temperature, supporting a folding defect conferred by the variants (FIG. 3C). Treatment with a proteasome inhibitor, bortezomib, increased WFS1 protein levels from both variants and the fold change for p.P885L was higher than p.R558C (FIG. 3D), indicating that proteasomal degradation of p.R558C is less than p.P885L. To confirm this observation, we performed a cycloheximide (CHX) chase assay using HA-tagged WFS1 variants. After inhibiting translation of nascent protein by CHX treatment, the protein levels of p.R558C and p.P885L were rapidly decreased within 2 hours (FIG. 3E). However, the rate of p.P885L decay was higher than p.R558C (FIG. 3E). Also, the basal expression of p.P885L was lower before CHX treatment compared to WT and p.R558C, all consistent with more rapid degradation of p.P885L (FIG. 3E). Next, we examined if the WFS1 variants endogenously expressed in cells would show similar post-translational stabilities. We obtained peripheral blood mononuclear cells (PBMCs) from three subjects carrying pathogenic variants in the WFS1 gene (W024: c.1672C>T, c.1672C>T; W392: c.1672C>T, c.1672C>T; W121: c.1672C>T, c.2654C>T) and generated iPSCs (Table 2). Consistent with our clinical investigation, subjects W024, W392, and W121 had mild phenotypes of Wolfram syndrome (Table 2). Western blot (WB) analysis revealed a reduction in WFS1 protein levels for W024, W392 and W121 compared to two control iPSC lines (BJFF.6 and AN1.1) (FIG. 3F). Of the three patient lines, WFS1 protein level in W121 was less than W024 and W392 (FIG. 3F). WFS1 mRNA was not significantly decreased in W024 and W392 compared to control lines but was reduced for W121 (FIG. 3G). We also performed the Actinomycin D (ActD) chase assay to determine WFS1 mRNA stabilities in each iPSC line. WFS1 mRNA decay was higher than that in one control line AN1.1, but similar with another control line BJFF.6 (FIG. 3H). On the other hand, corresponding to endogenous WFS1 expression, WFS1 mRNA in W121 was more unstable than both control lines (FIG. 3F). Taken together, the WFS1 c.1672C>T, p.R558C variant led to reduced expression of defective WFS1 protein, which was driven by post- translation protein degradation, but not mRNA alterations, designating the variant as class A2.
A combination treatment of 4-PBA and TUDCA ameliorates cellular function in neural progenitor cells with c.1672C>T, p.R558C variant We first tested if a combination treatment with 4-PBA and TUDCA (P+T) stabilized WFS1 protein using the HiBiT tagged reporters. The incubation with P+T significantly increased the steady-state levels of WFS1 p.R558C protein, but not WT nor a NanoLuc control expressed from an identical plasmid backbone (FIG. 4B). Although the treatment slightly increased the steady-state levels of WFS1 p.P885L as well, it was not significant statistically (P=0.0697). We also screened the NCATS Pharmaceutical Collection (~2000 compounds), which includes approved drugs as well as 4-PBA, but not TUDCA and found a small number of compounds that increased WFS1 p.R558C protein level, of which disulfiram was the top hit, but the magnitude of effect was similar to P+T. We next compared endogenous WFS1 protein levels in iPSCs treated with P+T. The P+T treatment significantly increased WFS1 protein levels in iPSCs derived from all three patient lines (FIG. 4C). Of note, WFS1 protein levels in W024 and W392 were restored as great as control lines (FIG. 4C). Additionally, mRNA level was increased by the P+T treatment (FIG. 4D). We previously described organelle dysfunction followed by cell death in neural progenitor cells (NPCs) differentiated from iPSCs derived from patients with typical Wolfram syndrome (Lu S, et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(49):E5292-301). NPCs differentiated from the three patient lines and control line (AN1.1) express NPC markers, NESTIN and SOX1 (FIG. 4E and FIG. 5A). They showed a similar pattern of WFS1 expression in iPSCs of these lines (FIG. 5B). Interestingly, the expression of ER stress marker genes, BiP and spliced XBP1 (sXBP1), were not greatly changed among the lines but CHOP, an ER stress-induced apoptosis gene, was significantly increased in each of the three patient lines (FIG. 5C). The other ER stress-induced apoptosis gene, TXNIP, was increased in W392 and W121 compared to AN1.1 (FIG. 5A). Next, we examined if a combination treatment of 4-PBA and TUDCA would restore organelle functions in NPCs derived from the three patient iPSC lines. The expression of BiP and sXBP1 were not affected by the P+T treatment, whereas CHOP and TXNIP were
significantly decreased in each of the three patient lines (FIG. 4F). We also measured the oxygen consumption rate (OCR) of NPCs to further assess mitochondrial function. Increased OCRs were observed throughout the assay in each of the three patient lines with the P+T treatment (FIG. 4G). To investigate whether increased OCR was caused by increased mitochondrial number or improved mitochondrial function, we measured mitochondrial DNA contents and mitochondrial membrane potentials in the NPCs treated with or without P+T. Interestingly, mitochondrial DNA was increased in W024 and W392 NPCs by the treatment (FIG. 7A), whereas the mitochondrial membrane potentials were not affected (FIG. 7B). In W121 NPCs, both mitochondrial DNA and membrane potentials were increased by the treatment (FIGs. 7A and 7B). Besides these improvements, the P+T treatment inhibited apoptosis, as indicated by caspase 3/7 activity and cleaved-caspase 3 protein levels, in each of the three patient lines (FIG. 4H and FIG. 7C). To define if a combination treatment of 4-PBA and TUDCA is valuable, we compared P+T efficacies with a single treatment with either 4-PBA or TUDCA. The P+T effect on endogenous WFS1 protein levels was the greatest in each of the three patient iPSC lines (FIG. 6A). Of note, WFS1 protein levels were significantly increased in W392 and W121 by the P+T treatment compared to a single treatment with each compound (FIG. 6A). The expression of ER stress-induced apoptosis genes was similar regardless of single or combination treatments in W024 and W392 NPCs, whereas only the P+T treatment significantly decreased ER stress-induced apoptosis gene expression in W121 (FIG. 6B). Mitochondrial DNA was not greatly changed by any single treatment in each of the three patient lines. Although we confirmed the increase of mitochondrial membrane potentials in W121 NPCs by the P+T treatment; it was not observed by a single treatment with each compound (FIG. 7B). Lastly, a single treatment with 4-PBA inhibited apoptosis in all three patient lines and TUDCA also decreased apoptosis in W392 (FIG. 4H and FIG.7C). However, the magnitude of inhibition was the largest in the P+T treatment in each of three patient lines (FIG. 4H and FIG. 7C). In addition, we confirmed the P+T treatment reduced caspase 3/7 activity in NPCs derived from patients with typical Wolfram syndrome as well (FIG. 8A and 8B). In summary, a combination treatment of 4-PBA and TUDCA increased WFS1 expression and inhibited apoptosis by mitigating ER stress and mitochondrial dysfunction, which was beneficial more than a single treatment of either 4-PBA or TUDCA alone although there were some variabilities among cell lines. A combination treatment of 4-PBA and TUDCA improves insulin secretion and survival in SC-β cells with WFS1 c.1672C>T, p.R558C variant The majority of patients with Wolfram syndrome develop diabetes mellitus due to the pathogenic WFS1 variants causing detrimental effects in pancreatic β cells (Fonseca SG, et al. WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic {beta}-Cells. The Journal of biological chemistry. 2005;280(47):39609-15; Fonseca SG, et al. Wolfram syndrome 1 gene
negatively regulates ER stress signaling in rodent and human cells. The Journal of clinical investigation. 2010;120(3):744-55; Abreu D, et al. Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival. Laboratory investigation; a journal of technical methods and pathology. 2020;100(6):849-62.). To evaluate the impact of the WFS1 c.1672C>T, p.R558C variant on β cells, we generated stem cell–derived pancreatic islets (SC-islets) from W024 and W121 iPSCs, and AN1.1 iPSCs as a control. We previously developed a 6-stage differentiation strategy, incorporating cytoskeleton modulation, to produce SC-islets containing hormone-secreting endocrine cell types, including insulin- positive stem cell-derived β (SC- β), glucagon-positive stem cell-derived α (SC-α), and somatostatin-positive stem cell-derived δ (SC-δ) cells. The W024 and W121 Stage 6 SC- islets produced C-peptide+ cells co-expressing β cell differentiation marker (NKX6.1) and committed endocrine cell marker (CHGA). The β cell population was similar between W024 and control SC-islets, but reduced in the W121 line (FIG. 9A and B). WFS1 protein was expressed in SC-islets derived from all three lines, with greater expression detected in control SC-islets (FIG. 9C). Of note, WFS1 protein level was significantly higher in W024 SC-islets when compared to W121 (FIG. 9C). However, both patient-derived SC-islets (W024 and W121) showed a significant reduction of WFS1 mRNA levels (FIG. 9D), which was not observed in W024 iPSCs and NPCs (FIG. 3G and FIG. 5B). We previously demonstrated the robust increase of WFS1 expression during the SC-islet differentiation from stage 5 to stage 6, suggesting that WFS1 expression in SC-islets could be much higher than iPSCs and NPCs. Previous studies showed WFS1 deficiency causes mild dilation of ER in β-cells (Riggs AC, et al. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005;48(11):2313-21; Akiyama M, et al. Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. Diabetologia. 2009;52(4):653-63; Hatanaka M, et al. Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic beta-cells. Hum Mol Genet. 2011;20(7):1274-84). Electron microscopic analyses displayed well-formed ER structures in AN1.1 SC-islets (FIG. 10). On the other hand, ER in W024 and W121 SC-islets were distorted, fragmented, and dilated (FIG. 10). We tested the functional capacity of the SC-islets in response to high glucose (20 mM) using the glucose stimulated insulin secretion (GSIS) assay. Throughout GSIS, W024 and W121 SC-islets secreted less insulin compared to control SC-islets. W024 SC-islets were able to increase their insulin secretion in response to the glucose stimulus, whereas W121 SC-islets were not capable of a glucose-stimulated response (FIG. 9E). These data suggest the WFS1 c.1672C>T, p.R558C variant has a milder effect on β cell insulin secretion than the WFS1 c.2654C>T, p.P885L variant. Next, we tested if the P+T treatment is effective in ameliorating W024 and W121 SC- islet dysfunction (FIG. 9F). WFS1 protein expression was restored in the treated SC-islets, as observed in both the W024 and W121 iPSCs (FIG. 9G). We observed the dilated ER was remitted in some W024 and W121 SC-islet cells treated with P+T (FIG. 10). In addition, the
P+T treatment greatly inhibited cell death in the W024 and W121 SC-islets (FIG. 9H). As expected with greater WFS1 protein, the insulin secretion of W024 and W121 SC-islets in low and high glucose was increased by the P+T treatment (FIG. 9I). In summary, P+T treatment restored WFS1 expression and increased insulin secretion capabilities of W024 and W121 SC-islets. Cellular stress is mitigated by a combination treatment of 4-PBA and TUDCA in SC-islets with WFS1 c.1672C>T, p.R558C variant We performed multiplexed single-cell RNA sequencing (scRNA-seq) using the 10x Genomics platform to investigate genotype-phenotype correlations and an efficacy of the P+T combination treatment on SC- β cells more precisely. We utilized Cell Hashing, which applied oligo-tagged antibodies to the cell surface proteins of individual samples, thus allowing for detection of individual samples within a pooled cell population. We sequenced four biological replicates per cell line from independent differentiations, treated with or without P+T for 7 days. In total, we sequenced 16 samples with 8 samples in each pooled population which were submitted separately based on the cell line. In total, we sequenced 13,951 Stage 6 SC-islet cells differentiated from W024 and W121 iPSCs to study the effects of P+T treatment (W024: 2,619 cells, W024, P+T: 3,158 cells, W121: 3,625 cells, and W121, P+T: 4,549 cells, 4 biological replicates for each sample). The scRNA-seq data was analyzed using dimensionality reduction and unsupervised clustering to classify individual cells into cell populations based on similarities in their transcriptome profiles. The cell types were identified by aligning the top upregulated genes in each cell cluster population with published pancreatic transcriptome data. After identifying the β cell population in each sample, we combined the 2,329 SC- β cells from the four experimental conditions (W024: 377 cells, W024, P+T: 220 cells, W121: 749 cells, and W121, P+T: 680 cells) and performed Principal Component Analysis (PCA) and unsupervised clustering. The β cells clustered together based on genetic background, regardless of combination treatment, suggesting the β cell transcriptional profile was not greatly changed in response to P+T. MT1X and ERO1B were highly expressed in W121 SC- β cells treated with P+T compared to untreated. We performed gene set enrichment analysis (GSEA) on the SC-β cells. Gene sets pertaining to NMD, ubiquitination-mediated protein degradation, and oxidative stress were enriched in the untreated SC- β cells compared to the P+T-treated SC- β cells. Interestingly, we found the inflammation and the selective mitochondrial autophagy (mitophagy) pathways were also enriched in the untreated SC- β cell population. Gene sets pertaining to apoptosis and ER stress were enriched in the untreated SC- β cells. Of note, gene sets related to insulin secretion, and β cell development were enriched in the P+T-treated SC- β cell population. Additionally, gene sets related to regulation of cytosolic K+ and Ca2+ levels were increased, which play an important role in β cell differentiation and function. Collectively, P+T treatment mitigated cellular stress increased by pathogenic WFS1 variants without changing
β cell identity, which resulted in increased β cell and insulin secretion in W024 and W121 SC-β cells. A combination treatment of 4-PBA and TUDCA delays the diabetic phenotype progression in Wfs1 deficient mice Finally, we verified the efficacy of our combination treatment with an in vivo study. The field lacks a c.1672C>T, p.R558C variant WFS1 mutation mouse model. Therefore, we employed 129S6 whole body Wfs1-knockout (Wfs1 KO) mice. This mouse model develops progressive glucose intolerance during adolescence, hence a mouse model of Wolfram syndrome (Abreu D, et al. Wolfram syndrome 1 gene regulates pathways maintaining beta- cell health and survival. Laboratory investigation; a journal of technical methods and pathology. 2020;100(6):849-62.). We confirmed Wfs1 KO mice developed glucose intolerance at 5-6 weeks old (FIG. 11A and 11B). In addition, Wfs1 KO mice did not show glucose-stimulated increase of the serum insulin level, which was lower than that of WT (FIG. 12A). We treated the mice at 5-6 weeks old with food containing 4-PBA and TUDCA (4-PBA: 0.338% and TUDCA: 0.225%, refer to P+T chow) for one month. Both groups of Wfs1 KO mice consumed similar amount of chow. After feeding for one month, Wfs1 KO mice fed with control chow developed more severe glucose intolerance (FIG. 11A and 11B). Conversely, an intraperitoneal glucose tolerance test (IP-GTT) blood glucose curve was similar to the baseline outcome in Wfs1 KO mice fed with P+T chow (FIG. 11A and 11B), indicating that P+T chow delayed the progression of the diabetic phenotype. Body weight and insulin sensitivity were not greatly changed by the P+T chow. The basal level of serum insulin (0min) was higher in Wfs1 KO mice fed with P+T chow as compared to Ctrl chow (FIG. 12F). Compared to baseline, serum insulin level at 30 min following glucose injection was decreased in Wfs1 KO mice fed with Ctrl chow, whereas it was similar in the mice fed with P+T chow (FIG. 12G). Collectively, we observed delays in the Wolfram diabetic phenotype in Wfs1 KO mice when using the P+T treatment. Therefore, we expect the combination treatment to be efficacious against diabetic Wolfram phenotypes caused by the WFS1 c.1672C>T, p.R558C variant in vivo. Example 2. A Phase II Study of Safety and Efficacy of AMX0035 in Adult Patients with Wolfram Syndrome Study Design: Single-centre, open-label study where up to 12 participants are treated with AMX0035 for up to 24 weeks. The study consists of a Screening period of up to 4 weeks, a 24-week Open-Label Treatment Period, and a post-treatment follow-up visit at Week 28. Upon completion of Screening and Baseline procedures, eligible participants will receive standard of care + AMX0035 at predefined doses.
Eligible participants are enrolled into the Open-Label Treatment Period of the study on Day 1 and receive their first dose of study drug. During the first 3 weeks of dosing, participants take 1 sachet of AMX0035 daily and if tolerated will increase to 1 sachet twice daily (morning and evening). Participants will return to the study site every approximately 12 weeks for study procedures and assessments, and blood collection. Study Objectives: Primary Objectives · To evaluate the effect of AMX0035 on residual beta cell functions by monitoring C-peptide levels during a 0-240 minutes mixed-meal tolerance test (MMTT) · To assess the safety and tolerability of AMX0035 administered orally for up to 24 weeks in adult patients with diabetes mellitus due to Wolfram syndrome Secondary Objectives · Estimate the treatment effect size of AMX0035 on best-corrected visual acuity for both eyes measured on the LogMar scale by sight tests in clinic using Snellen chart · To evaluate the effect of AMX0035 by tracking changes in total daily insulin dose (with percentage basal versus bolus) · To evaluate the effect of AMX0035 by tracking the time in good glucose range (70-180 mg/dL), time below range (54-69 mg/dL), time above range (181-250 mg/dL) measured by continuous glucose monitoring (CGM) · To evaluate the effect of AMX0035 by tracking the reduction of HbA1c Exploratory Objectives To evaluate the effects of AMX0035 on: · Wolfram Unified Rating Scale (WURS) · Scale for the assessment and rating of ataxia (SARA) · Visual function using Visual Functioning Questionnaire – 25 (VFQ-25) · Diabetic measurements · Blood biomarker (panel) levels of neurodegeneration and neuroinflammation · Changes in retinal pathologies, based on optical coherence tomography (OCT), including OCT-angiography · Global Impression Scales, patient reported global impression of change (PGIC) and clinician reported global impression of change (CGIC) · Most bothersome symptom (MBS) Endpoints: Safety Endpoints · Incidence and severity of adverse events (AE) and serious adverse events (SAEs) · Incidence of abnormalities in clinical laboratory assessments Efficacy Endpoints
Primary Efficacy Endpoint · C-peptide Area Under the Curve (AUC) Response to a 0-240 minutes MMTT at week 24 (and additional timepoints) · Change from Baseline in ΔC-peptide at Week 24 (and additional timepoints) using a 0-240 minutes MMTT Secondary Efficacy Endpoints · Change in Baseline (to Week 24) on best-corrected visual acuity for both eyes measured on the LogMar scale by sight tests in clinic using Snellen chart. Values are taken for each eye after correction, and can range from 0, which represents perfect vision (values of -0.1 and -0.2 are also possible representing better than perfect vision), to +2 which represents near blindness. Increases in LogMAR represent deterioration. · Change from Baseline (to Week 12 and Week 24) of exogenous insulin dose per kg body weight and 24 hours (with percentage basal versus bolus) change between Baseline and subsequent visits · Change from Baseline to Week 24 in overall time in glucose range (70-180 mg/dL) measured by CGM · Time in good range (TIR), % of readings and time 70-180 mg/dL · Time below range (TBR), % of readings and time 54-69 mg/dL · Time above range (TAR), % of readings and time 181-250 mg/dL · Change from Baseline to Week 24 in HbA1c level Exploratory Efficacy Endpoints · Change from Baseline in: o WURS o SARA o VFQ-25 o OCT measurements o CGI-C o PGI-C o MBS o Blood biomarker (panel) levels of neurodegeneration and neuroinflammation o Diabetic measurements, including fasting glucose, fasting proinsulin, AUC c- peptide/AUCglucose, delta proinsulin o Change from Week 24 to Week 28 in C-peptide levels Study Population: Inclusion Criteria 1. The participant has a definitive diagnosis of Wolfram syndrome, as determined by the following:
a. Documented functionally relevant recessive mutations on both alleles of the WFS1 gene based on historical test results (if available) or from a qualified laboratory at Screening. 2. A stimulated C-peptide level of ≥0.2 ng/mL during the Screening Visit 3. Insulin dependent diabetes mellitus due to Wolfram syndrome 4. At least 17 years of age at the time of written informed consent 5. Women of child-bearing potential (e.g., not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control* for the duration of the study and 6 months after last dose of study drug. Women must not be planning to become pregnant for the duration of the study and 6 months after the last dose of study drug 6. Men must agree to practice contraception* for the duration of the study and for at least 6 months after the last dose of study drug. Men must not plan to father a child or provide sperm for donation for the duration of the study and 6 months after the last dose of study drug *Acceptable birth control methods for use in this study are: a. Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants b. Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm) c. Intrauterine device (IUD) d. Abstinence (no heterosexual sex) Unique partner who is surgically sterile (men) or not of childbearing potential (female) Exclusion Criteria 1. Clinically significant non-Wolfram related central nervous system (CNS) involvement which is judged by the Investigator to likely interfere with the accurate administration and interpretation of protocol assessments 2. Clinically significant unstable medical condition (other than Wolfram syndrome) that would pose a risk to the participant if they were to participate in the study, according to Investigator judgment 3. Clinically significant, in the opinion of the Investigator, infection or inflammation at the time of Screening or admission. If infection and inflammation has been cured, participants can be rescreened 4. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) at the time of Screening or admission
5. Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair the ability of the participant to provide informed consent and follow instructions, according to Investigator judgment 6. Any major surgery within 4 weeks of Screening 7. Unable to comply with the protocol, (e.g., has a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioral instability, is unable to travel to site as required for study evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator 8. History of known allergy to phenylbutyrate (PB) or bile salts 9. Abnormal liver function defined as aspartate transaminase (AST) and/or alanine transaminase (ALT) > 3 times the upper limit of the normal (ULN) 10. Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 11. Anemia with hemoglobin (Hgb) concentration < 10.0 g/dL at screening 12. Pregnant women or women currently breastfeeding 13. Current biliary disease which may lead to biliary obstruction or impedes biliary flow including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, abscess of the gallbladder 14. Any History of heart failure per New York Heart Association (NYHA) 15. History of or family history of breast and/or ovarian cancer 16. Participant under severe salt restriction where the added salt intake due to treatment would put the patient at risk, in the Investigator’s judgment 17. Received treatment with any investigational drug or device within the 30 days prior to Screening/study entry 18. Received blood product transfusions within 90 days prior to Screening 19. Previous treatment with gene or cellular therapy 20. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory determinations beyond what is consistent with the target population in the opinion of the PI. 21. Clinically significant abnormality on 12-lead ECG prior to study treatment administration, confirmed by repeat.
22. Any history of clinically significant suicidal ideation and/or behavior within 1 year of Screening as determined by the Investigator. 23. Anything that, in the opinion of the Investigator, precludes the participant's full compliance with or completion of the study 24. Currently or previously treated within the last 30 days prior to Screening or planned exposure to any prohibited medications listed below. Except for the study drug, any investigational therapy being used or evaluated for the treatment of Wolfram syndrome is prohibited beginning 30 days (or 5 half-lives, whichever is longer) prior to the first dose (or screening, in case same visit) and throughout the trial. Use of any gene or cellular therapy (such as NurOwn, Q-Cells, T regulatory therapy) prior to this trial excludes participants from enrollment. These are also prohibited during the trial. Unless approved by the Investigator in consultation with the Sponsor, participants should not receive the following medications (not a comprehensive list) described in Table 1. Table 1. List of Prohibited Medication
Study Treatment: All participants will receive oral AMX0035 treatment. For the first 3 weeks of dosing, participants will take 1 sachet daily and if tolerated will increase to 1 sachet twice daily (morning and evening). AMX0035 will be supplied by the Sponsor to the site pharmacy as a carton box containing single use sachets. Each AMX0035 sachet contains active ingredients (3 g PB and 1 g taurursodiol [TURSO]) and excipients in a powder formulation. Study drug is mixed with ~1 cup of water and taken orally. Duration of Study and Treatment: Treatment will last up to 24 weeks. The planned overall study duration is up to 32 weeks for participants who complete the study. Individual Stopping Criteria: All AEs, safety laboratory results and use of concomitant medications will be monitored closely by the Investigator throughout the study. If any clinically significant laboratory or clinical abnormality occurs, the participants will be monitored closely until resolution or clinically stable. Management of dose limiting treatment-emergent adverse events (TEAE), intolerable to the participant and possibly related to study drug in the opinion of the Investigator, may be managed by stepwise dose reduction(s) to a lower dose of 1 sachet of study drug per day. If this first level dose reduction does not result in improvement within 7 to 14 days, the dose may be reduced to 1 sachet of study drug once every 2 days. The Investigator may decide at any time to interrupt treatment. If a participant demonstrates treatment-emergent signs of neurotoxicity including, but not limited to, vomiting, nausea, headache, dizziness, somnolence, dysgeusia hypoacusis,
disorientation, confusion, memory loss, neuropathy, possibly related to study drug in the opinion of the Investigator, the Investigator should consider a dose reduction or interruption. Any dosage adjustment, including the reason for and dates of adjustment, will be documented in the source documentation and the electronic case report form (eCRF) Any dose modifications may be discussed with the Medical Monitor. The new regimen, reduced dose or interruption, may be maintained for as long as necessary until the event improves. The Investigator may then choose to resume the higher dosage or maintain the participant at a reduced dosage. Any dose interruptions should be discussed with the Medical Monitor. Recurrence of the dose-limiting TEAE upon re-introduction of the study drug will result in stopping treatment permanently. The following AEs will trigger temporary dose interruption: · Persistent diarrhea: Persistence of several (>5) loose, watery stools for more than 3 days after the start of the treatment associated with the need of rehydration therapy. · Treatment emergent increase in serum creatinine or liver enzymes according to the following guidance: o Confirmed increase > 50% from Baseline in serum creatinine o ALT or AST > 8 x ULN o ALT or AST > 5 x ULN for more than 2 weeks o ALT or AST > 3 x ULN and (serum total bilirubin > 2 x ULN or international normalized ratio > 1.5) o ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) · Treatment emergent Grade 3 AE per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 unless otherwise specified. Diagnostic tools and rating scales The diagnostic tools and rating scales include the following: • 0-240 minutes MMTT (Primary Efficacy Endpoint) The MMTT tests measure residual β-cell functions (Buss 1982). The night before the MMTT, the participant will receive an evening dose of Lantus insulin and fast from midnight until the test at 8:00 AM. The mixed meal consists of 6 mL/kg (maximum 360 mL) of Boost Original (Société des Produits Nestlé S.A., Vevey, Switzerland). The following instructions should be followed: · Prior to the MMTT, participants should not take short-acting insulin, short-acting GLP-1 receptor agonists, metformin, and SGLT inhibitors · The timeframe for consumption of Boost Original is within 5 minutes · Blood for glucose and C-peptide measurement will be drawn at Times -10, 0, 15, 30, 60, 90, 120, 180, and 240 minutes with ±5 minutes sample collection windows · If a participant’s fasting glucose exceeds 11.1 mmol/L, the test will not be performed, but fasting glucose and C-peptide will be obtained
· Participants using continuous subcutaneous insulin infusion (CSII) for their diabetes management should receive appropriate insulin adjustment leading up to the MMTT test · Appropriate clinical safety measure should be put in place to ensure safety of the participants during the 4h MMTT. o The PI and study staff is responsible for appropriate clinical monitoring over the entire study day duration, this includes safety monitoring (e.g. ketone monitoring) during the MMTT. In the opinion of the PI, appropriate clinical safety measure should be put in place to ensure safety of the participants during the 4h MMTT. • Diabetic Measurements The primary responsibility for diabetes management will remain with the treating or referring diabetes care provider, but the Investigator study team will provide close additional support through interaction by phone as needed. Diabetes management will be monitored by the Investigator study staff with phone calls between study visits as needed. Diabetic measurements will include: · fasting glucose, fasting proinsulin, AUC C-peptide/AUC-glucose, delta proinsulin The diabetic measurements will allow for the following: · continuous glucose monitoring (CGM) · tracking changes in total daily insulin dose · tracking the reduction of HbA1c • WURS The WURS (Nguyen 2012) is a clinical scale to measure disease severity and progression in Wolfram syndrome. The scale consists of three (3) domains: · Domain A = Physical – Physician Rated · Domain B = Physical – Parent Rated · Domain C = Behavioral – Parent Rated. The Physical domains are rated 0 – 4, with zero (0) corresponding to the absence of symptoms, and four (4) to the presence of symptoms with the greatest severity. The behavioral domain is rated 0 – 3, with zero (0) corresponding to a normal behavior, and three (3) indicating the presence of a disorder of greater severity. • SARA The Scale for the Rating and Assessment of Ataxia (Subramony 2007) is an 8-item performance-based scale, yielding a total score 0 (no ataxia) to 40 (most severe ataxia). The scores are based on participant performance of: 1) gait, 2) stance, 3) sitting, 4) speech disturbance, 5) finger chase, 6) nose-finger test, 7) fast alternating hand movements, 8) heel- shin slide. • VFQ-25 The 25-Item National Eye Institute Visual Functioning Questionnaire (VFQ-25) is designed to measure vision-related functioning and the influence of vision-related problems. The VFQ-25 represents 11 vision-related constructs and contains up to 39 items, plus an additional single-
item general health rating question. Scoring involves raw scores being converted to a 100-point scale with higher scores associated with worse performance. • CGI-C The CGI-C rates improvement by 7 categories: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. These assessments are administered to the participant by the Site (Study PI). • PGI-C Participants will evaluate the change in their Wolfram syndrome-related symptoms since initiation of study drug by choosing one of seven responses. The PGI-C is a 7-point response scale. The participant will be asked by the Investigator or qualified designee to rate their change in status using the following 7-point scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. The responses of "Very much improved," "Much improved," "Minimally improved" and "No change" on the PGI-C will be used to define responders. • MBS The patient-identified Most Bothersome Symptom (MBS) is identified at Screening, where participants describe the MBS they associate with Wolfram syndrome. At follow-up visits, participants will be asked to rate the overall change in that symptom since study initiation, using a 7-item Likert-type scale ranging from “very much improved” to “very much worse”: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. It is administered to the participant by a clinician. • OCT Optical Coherence Tomography (OCT) is a non-invasive imaging test of the eye. OCT uses light waves to take cross-section pictures of the participants retina for the diagnosis and study of eye disorders. The OCT measurements study will also include angiography and testing for visual acuity. A detailed OCT manual will be included as separate document. • C-SSRS The C-SSRS is a systematically administered instrument developed to track suicidal AEs across a treatment study. The instrument is designed to assess suicidal behavior and ideation, track and assess all suicidal events, as well as the lethality of attempts. Additional features assessed include frequency, duration, controllability, reason for ideation, and deterrents. The C-SSRS is considered a low-burden instrument as it takes less than 5 minutes to administer. It is administered to the participant by the Investigator or qualified designee. Any participant noted to have suicidal ideation with plan within the prior month, either via answering "yes" to Questions 4 or 5 to the suicidal ideation portion of the C-SSRS or via
clinical interview, will be evaluated immediately by the Investigator. The Medical Monitor and Sponsor will also be informed. Appropriate steps will be taken to protect the participant, including but not limited to possible discontinuation (decided by either the Investigator or Medical Monitor) from the study and referral for appropriate psychiatric care. Any such participant at Screening or on Day 1 will also be excluded from the study.
Claims
WHAT IS CLAIMED IS: 1. A method of treating one or more symptoms of Wolfram syndrome in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a combination of TURSO and sodium phenylbutyrate.
2. The method of claim 1, wherein the subject has or is at risk for developing diabetes.
3. The method of claim 2, wherein the diabetes is insulin-dependent diabetes.
4. The method of claim 2, wherein the diabetes is juvenile onset diabetes.
5. The method of any one of the above claims, wherein the subject has or is at risk for developing optic nerve atrophy.
6. The method of any one of the above claims, wherein the subject has or is at risk for developing a hearing impairment.
7 The method of any one of the above claims, wherein the subject has one or more mutations in the Wolframin (WFS1) gene.
8. The method of claim 7, wherein the subject has the c.1672C>T, p.R558C mutation in the WFS1 gene.
9. The method of claims 7 or 8, wherein the subject has the c.2654C>T, p.P885L mutation in the WFS1 gene.
10. The method of any one of the above claims, wherein the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene.
11. The method of any one of the above claims, wherein the TURSO and the sodium phenylbutyrate are administered once a day or twice a day.
12. The method of any one of the above claims, wherein TURSO is administered to the subject at a dose of about 5mg/kg to about 100 mg/kg.
13. The method of any one of the above claims, wherein sodium phenylbutyrate is administered to the subject at a dose of about 10mg/kg to about 400 mg/kg.
14. The method of any one of the above claims, wherein the TURSO is administered at an amount of about 0.5 to about 5 grams per day.
15. The method of any one of the above claims, wherein the sodium phenylbutyrate is administered at an amount of about 0.5 grams to about 10 grams per day.
16. The method of any one of the above claims, comprising administering to the subject 1 gram of TURSO and 3 grams of sodium phenylbutyrate once a day or twice a day.
17. The method of any one of the above claims, comprising administering to the subject 1 gram of TURSO once a day and 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering to the subject about 1 gram of TURSO twice a day and 3 grams of sodium phenylbutyrate twice a day.
18. The method of any one of the above claims, wherein the TURSO and the sodium phenylbutyrate are administered orally.
19. The method of any one of the above claims, wherein the TURSO and the sodium phenylbutyrate are formulated as a single powder formulation.
20. The method of any one of the above claims, further comprising administering one or more additional therapeutic agents to the subject.
21. The method of claim 20, wherein the one or more additional therapeutic agents is valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, or ER Ca2+ stabilizers.
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Citations (2)
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US20130274184A1 (en) * | 2011-10-11 | 2013-10-17 | The Trustees Of Columbia University In The City Of New York | Er stress relievers in beta cell protection |
US20210186990A1 (en) * | 2019-12-16 | 2021-06-24 | Amylyx Pharmaceuticals, Inc. | Methods and compositions for treating various disorders |
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- 2022-11-07 WO PCT/US2022/049125 patent/WO2024102114A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20130274184A1 (en) * | 2011-10-11 | 2013-10-17 | The Trustees Of Columbia University In The City Of New York | Er stress relievers in beta cell protection |
US20210186990A1 (en) * | 2019-12-16 | 2021-06-24 | Amylyx Pharmaceuticals, Inc. | Methods and compositions for treating various disorders |
Non-Patent Citations (1)
Title |
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KITAMURA RIE ASADA, MAXWELL KRISTINA G; YE WENJUAN; KRIES KELLY; BROWN CRIS M; AUGSORNWORAWAT PUNN; HIRSCH YOEL; JOHANSSON MARTIN : "Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome", JCI INSIGHT, 22 September 2022 (2022-09-22), XP093172845, DOI: 10.1172/jci. * |
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