WO2025199295A1 - Taurine and/or a prodrug thereof for the treatment of cystinosis - Google Patents

Abstract

Provided herein are methods for treating, preventing and/or ameliorating. cystinosis in a subject comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

Description

TAURINE AND/OR A PRODRUG THEREOF FOR THE TREATMENT OF CYSTI NOSIS

All patents, patent applications and publications cited herein are hereby incorporated by reference in their entireties. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.

FIELD

Provided herein are methods for treating, preventing and/or ameliorating cystinosis in a subject, comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

BACKGROUND

Cystinosis has been known since 1903, when Abderhalden described small, pale children who died of wasting and whose organs were shown to be riddled with microscopic crystals. Cystinosis is an intracellular condition that results from defective lysosomal cystine transport, leading to lysosomal cystine storage. The lysosomal cystine transporter, cystinosin, is encoded by CTNS, located at 17p13.3, and functions to move cystine from the lysosomal interior to the cytosol, where it can be reused for glutathione and protein synthesis. Many mutations have been described at this locus, however a large 57 kb deletion accounts for about half the cases descended from west European parents. The clinical phenotype in cystinosis is relatively unique: renal Fanconi syndrome with salt, water, glucose, amino acid and other small molecule losses; crystalline keratopathy and salt and pepper retinopathy; short stature and failure to thrive; photophobia; and ultimately renal death by age 10 years. Other elements include hypothyroidism, and later in life, muscle weakness, esophageal dysmotility, diabetes, deficient bone mineralization, and pulmonary involvement. It is treated symptomatically with salt and water replacement, and specifically, with cysteamine. Specific therapy for cystinosis was achieved in 1994 when the FDA approved cysteamine bitartrate as Cystagon forthe treatment of cystinosis.

Unfortunately, the structure of cysteamine includes a free thiol group, thus the drug has the odor and taste of rotten eggs, a feature of concern both to parents administering the treatment to children, and to subjects themselves who may find the offensive odor to be socially debilitating. In addition, cysteamine must be taken at least every 12 hours, e.g. in some cases, at least every 6 hours, and some patients require gastric tubes to tolerate the medicine. Although cysteamine has been FDA approved since 1994, there are problems with this therapy: 1 ) It does not prevent renal failure, but merely delays the onset, for most patients 2) its repugnant thiol odor and taste causes both gastrointestinal and compliance problems and social concerns in children as they reach adolescence 3) it requires frequent, multiple doses throughout a patient’s lifespan and 4) it does not ameliorate short stature, muscle weakness, pulmonary involvement, the renal Fanconi syndrome, nor elements of premature aging. Other adverse phenotypic developments not responsive to systemic cysteamine therapy include corneal crystals, retinopathy, inflammation, hypercholesterolemia, metabolic bone disease, male infertility, vascular calcifications, pulmonopathy, hypothyroidism and diabetes.

For these reasons, there is a need for an improved treatment for cystinosis.

SUMMARY

The invention provides a method of treating, preventing and/or ameliorating cystinosis in a subject, the method comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

The invention also provides for the use of an effective amount of taurine and/or a prodrug thereof administered for treating, preventing and/or ameliorating cystinosis in a subject. The invention also provides taurine and/or a prodrug thereof for use in treating, preventing and/or ameliorating cystinosis in a subject, wherein the taurine is formulated for administration.

The invention also provides a supplement for cystinosis comprising taurine and/or a prodrug thereof, wherein the supplement is formulated for administration to a subject.

DEFINITIONS

Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, some preferred methods, compositions, devices, and materials are described herein. However, before the present materials and methods are described, it is to be understood that this invention is not limited to the particular molecules, compositions, methodologies or protocols herein described, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the embodiments described herein.

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. However, in case of conflict, the present specification, including definitions, will control. Accordingly, in the context of the embodiments described herein, the following definitions apply.

As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a therapeutic” is a reference to one or more therapeutics and equivalents thereof known to those skilled in the art, and so forth.

As used herein, the term “comprise” and linguistic variations thereof denote the presence of recited feature(s), element(s), method step(s), etc. without the exclusion of the presence of additional feature(s), element(s), method step(s), etc. Conversely, the term “consisting of” and linguistic variations thereof, denotes the presence of recited feature(s), element(s), method step(s), etc. and excludes any unrecited feature(s), element(s), method step(s), etc., except for ordinarily associated impurities. The phrase “consisting essentially of” denotes the recited feature(s), element(s), method step(s), etc. and any additional feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many embodiments herein are described using open “comprising” language. Such embodiments encompass multiple closed “consisting of” and/or “consisting essentially of” embodiments, which may alternatively be claimed or described using such language.

As used herein, the term “prodrug” is intended to mean a biologically inactive compound which can be metabolized in the body to produce a drug. For example, prodrugs of taurine are biologically inactivate when administered to a subject. Once administered, a prodrug of taurine metabolizes to taurine via the phosphotriesterase- related (PTER) enzyme (see Wei et al., A PTER-dependent pathway of taurine metabolism linked to energy balance. bioRxiv. 2024 Mar 22; 2024). In a preferred embodiment, a prodrug is any taurine conjugate which is released to form free taurine.

In a preferred embodiment, the prodrug is an N-conjugate of taurine. In one embodiment, the prodrug is acetyl taurine (see Wei et al., A PTER-dependent pathway of taurine metabolism linked to energy balance. bioRxiv. 2024 Mar 22; 2024). In one embodiment, the prodrug is succinyl taurine (see Akira et al., LC-NMR identification of a novel taurine-related metabolite observed in (1 )H NMR-based metabolomics of genetically hypertensive rats. J Pharm Biomed Anal. 2010 Apr 6;51 (5): 1091 -6). In one embodiment, the prodrug is pyruvyl taurine. In one embodiment, the prodrug is alphaketoglutaryl taurine. In one embodiment, the prodrug is fumaryl taurine. In one embodiment, the prodrug is malyl taurine. In one embodiment, the prodrug is oxalyl taurine.

As used herein, the term “treating" is intended to mean alleviating at least one indication of a disease.

As used herein, the term “preventing" is intended to mean preventing a condition or disease from occurring in a subject who is at risk of having the condition or disease.

As used herein, the term “ameliorating” is intended to mean lessening of at least one indicator of the severity of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). Preferably, the subject is human. The methods of the invention are directed to treating, preventing and/or ameliorating cystinosis in a subject. The subject may therefore be described as a subject in need of treatment, prevention and/or amelioration of cystinosis.

As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be by enteral administration or parenteral administration. Enteral administration refers to administration to the gastrointestinal tract e.g. oral administration, rectal administration, administration using a nasogastric tube, nasointestinal tube, percutaneous endoscopic gastrostomy tube etc. Parenteral administration refers to administration in vivo that is outside the gastrointestinal tract e.g. such as injection (e.g., intravenous, intramuscular, subcutaneous, intrathecal), sublingual administration (under the tongue), inhalation (into bronchi) etc. A preferred route for enteral administration is oral administration. A preferred mode of parenteral administration is intravenous administration.

As used herein, the term “effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

As used herein, the terms “co-administration” and “co-administering” refer to the administration of at least two agent(s) (e.g., taurine and/or a prodrug thereof and one or more additional therapeutics) or therapies to a subject. In some embodiments, the coadministration of two or more agents or therapies is concurrent (e.g., in a single formulation/composition or in separate formulations/compositions). In other embodiments, a first agent/therapy is administered prior to a second agent/therapy. Those of skill in the art understand that the formulations and/or routes of administration of the various agents or therapies used may vary. The appropriate dosage for coadministration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, coadministration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and/or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent. Preferably, the one or more additional therapeutics is cysteamine.

As used herein, cystinosis refers to a metabolic disease characterized by an abnormal accumulation of the amino acid cystine in various organs of the body such as the kidney, eye, muscle, pancreas, and brain. Different organs are affected at different ages. There are three clinical forms of cystinosis. Infantile (or nephropathic) cystinosis; late-onset cystinosis; and ocular cystinosis. The latter form does not produce kidney damage. Infantile cystinosis is usually diagnosed between 6 and 18 months of age with symptoms of excessive thirst and urination, failure to thrive, rickets, and episodes of dehydration. Children with cystinosis also have crystals in their eyes (after one year of age) which may lead to photosensitivity. They also have an increased level of cystine in their white blood cells without adverse effect but allowing the diagnosis to be ascertained. Without specific treatment, children with cystinosis develop end-stage renal failure, i.e. , lose their kidney function, usually between 6 and 12 years of age. Without cysteamine treatment subjects can develop complications in other organs due to the continued accumulation of cystine throughout the body. These complications can include muscle wasting, difficulty swallowing, diabetes, and hypothyroidism. In a preferred embodiment, cystinosis is nephropathic cystinosis.

As used herein, the term “mg/kg/day” refers to milligrams of a substance per kilogram of body weight per day. In a preferred embodiment, the substance is taurine. For example, 20mg/kg/day of taurine refers to 20 milligrams of taurine per kilogram of a subject’s body weight per day. As used herein, the term “g/day” refers to grams of a substance per day. In a preferred embodiment, the substance is taurine. For example, 20g/day of taurine refers to 20 grams of taurine per day.

DETAILED DESCRIPTION

Provided herein are methods for treating, preventing and/or ameliorating cystinosis in a subject, the method comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

Cystinosis is caused by mutations or deletions in the gene CTNS. The CTNS gene encodes a seven-transmembrane lysosomal protein cystinosin. Cystinosin has two crucial roles.

The first role of cystinosin is as a cystine-proton symporter that transports cystine from the lysosomal lumen to the cytosol. In the cytosol, cystine is reduced to cysteine. Cysteine, a component of coenzyme A, is acted on by cysteine dioxygenase to form cysteine sulfonate which is decarboxylated by cysteine sulfonate decarboxylase to form hypotaurine. Hypotaurine is further metabolized to taurine by hypotaurine dehydrogenase Taurine is eliminated in the form of bile salts such as taurocholate, either via the urine or feces.

Subjects with cystinosis are unable to transport cystine due to defective cystinosin, resulting in cystine accumulation in the lysosomes of subjects. Cystinosis is a condition characterized by this accumulation of cystine.

Cysteamine (2-aminoethanethiol) is an FDA-approved drug for the treatment of cystinosis. Cysteamine, also known as 2-mercaptoethylamine or 2-aminoethanethiol, is the decarboxylated derivative of the amino acid cysteine. Cysteamine is a compound of the formula:

Cysteamine is generated in mammals by the degradation of coenzyme A. When coenzyme A is cleaved, pantetheine is generated, which is acted on by pantetheinase or vanin to form cysteamine. Cysteamine is converted to hypotaurine by cysteamine decarboxylase. Hypotaurine generated is further metabolized to taurine by hypotaurine deydrogenase. Cysteamine causes depletion of cystine from the lysosomes by forming a mixed disulfide with cystine in the lysosomes which resembles lysine and which can thus exit lysosomes on the intact lysine transporter. By allowing cystine to exit the lysosomes, cysteamine overcomes a major function of the defective cystinosin and treats cystinosis.

The second role of cystinosin is to alter mTOR (mammalian target of rapamycin) signaling. In addition to the clinical abnormalities, cystinosis displays abnormalities in cell physiology which contribute to the clinical phenotype. A list of these abnormalities include, but are not limited to:

- Loss of cell specialization

- Increased apoptosis

- Increase autophagy

- Aberrant intermediate metabolism including lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signalling

- Aberrant osteocyte development

- Aberrant myocyte development

- Cystine crystal inflammatory process

- Failure of proximal renal tubule cells to reabsorb small molecules

These abnormalities center around mTOR, a serine/threonine kinase and major regulator of cell metabolic activity. The primary biochemical/physiological defect in cystinosis is failure to supply cysteine to mTOR via cystinosin. The lysosomal membrane is a regulated docking surface for mammalian target of rapamycin complex 1 (mTORCI ) machinery, which integrates information on the nutritional status of the cell, such as amino acid supply, to regulate autophagy and cell differentiation. In the presence of cysteine, mTORCI is inactivated, which permits cell differentiation. Conversely, starvation (cysteine deprivation) activates mTORCI , which stops cell differentiation, leading to proximal tubule loss and ultimately renal failure. Additionally, when mTOR is starved of cysteine, it triggers mobilization of nutrient reserves by activating autophagy and increasing apoptosis, which contributes to impaired growth. A vacuolar ATPase (v- ATPase) proton pump is necessary for mTORCI activation by the amino acid cysteine, by engaging in amino acid-sensitive interactions with the Rag-Ragulator complex. Cystinosin interacts physically with almost all components of the v-ATPase, Ragulator complex and Rag proteins; these interactions require the fifth loop in cystinosin.

It has recently been discovered that the harm from cystinosis is not only due to the cystine accumulation in the lysosome but also from the absence of cysteine in the cytosol and failure of cystinosin to act with mTOR. Subjects with cystinosis are unable to inactivate mTOR signalling due to the lack of cysteine and defective cystinosin, resulting in suppression of cell differentiation and increased autophagy.

In subjects with cystinosis, mTOR is diverted from balancing cell nutritional needs when defective cystinosin precludes delivery of cyst(e)ine to the cytosol. The resulting cysteine deficiency stimulates Ragulator-Rag GTPase-dependent recruitment of mTOR and produces continuous activation. This state leads to failure of renal proximal tubule cells to differentiate. In cystinosis, failure of these cells to differentiate leads to the formation of atubular glomeruli, a recognized end stage of cystinosis.

In subjects with cystinosis, mutant cystinosin alters mTOR activation making it become constitutively active, and leading to the cystinosis phenotype. Phenotypic development results from several known aberrant cell functions: 1 ) Cystinosin is important for CMA (chaperone-mediated autophagy) activity. Autophagy is increased in cystinotic cells, resulting from mTOR response to assumed starvation in which cells revert to lysosomal degradation of endogenous proteins, particularly mitochondrial proteins, to provide a supply of free amino acids to allow continuation of protein synthesis. CMA impairment contributes to cell malfunction in cystinosis, highlighting the need for treatments complementary to current therapies that are based on decreasing lysosomal overload. 2) Cystinotic cells show increased apoptosis. Hyperactive apoptosis has been reported in nephropathic cystinosis cells since first described by Thoene in 2002 (Thoene et al., Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells. J Am Soc Nephrol. 2002) and subsequently found to affect proximal renal tubule cells (Thoene et al., 2004 Potential role of apoptosis in development of the cystinotic phenotype. Pediatr Nephrol. 2005 Apr;20(4):441 -6).This feature can explain much of the cystinosis phenotype, including short stature, muscle weakness, pulmonary insufficiency, diabetes and bone density issues.

Cysteamine has been shown to have no impact on mTOR signaling. Neither cysteine, N- acetylcysteine nor cysteamine blunt the constitutive activation of mTOR in cystinotic cells nor restore the normal equilibrium of mTOR between cell differentiation and cell proliferation. Although cysteamine compensates for a major function of cystinosin that is missing in cystinosis patients by allowing cystine to exit the lysosomes, cysteamine does not replace cysteine or defective cystinosin and thus has no impact on mTOR signaling. Therefore, cysteamine alone cannot reverse all elements of cystinosis. This agrees with the clinical finding that cysteamine does not affect the renal Fanconi Syndrome in cystinosis patients.

Taurine, also known as 2-aminoethanesulfonic acid, is an aminosulfonic acid found in many tissues. Taurine is one of the most abundant naturally occurring amino acids in humans. Taurine has the formula:

With recognition of the potential for taurine to ameliorate aging, together with his extensive knowledge relating to cystinosis, the inventor was surprisingly able to identify that taurine itself would be a beneficial therapeutic for patients with cystinosis. The distinct beneficial effect of administering taurine to cystinosis patients is surprising, as cysteamine is known to degrade to taurine in treated cystinosis patients in vivo, and therefore administration of taurine itself might be considered ineffective. In line with this, taurine was shown to be excreted in the urine of cysteamine treated patients in 1987 (see Thoene JG, et al., Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest. 1976 Jul;58(1 ):180-9 and Han et al., The role of taurine in renal disorders. Amino Acids (2012) 43:2249-2263). However, as taurine has very recently been shown to stimulate mTOR activation in healthy patients (see Gao X et al.,. Cul5 mediates taurine- stimulated mTOR mRNA expression and proliferation of mouse mammary epithelial cells. Amino Acids. 2023 Feb;55(2):243-252) when cysteamine did not, the inventor has identified a new therapeutic for cystinosis patients, that may be used alone, or in addition to cysteamine treatment, to correct constitutive mTOR signaling. The effect of taurine (compared to cysteamine) on mTOR activity in cystinosis patients would not have been expected previously.

Subjects with cystinosis have low plasma taurine due to the two following factors:

1 ) Cysteine is the substrate for cysteine sulfinate decarboxylase (CSD) , the rate limiting step in taurine synthesis, and the major endogenous source of taurine. Cysteine is significantly limited by the defect in cystinosin that precludes delivery of cystine to the cytosol where it is reduced to cysteine and supplies mTOR and CSD with cysteine. CTNS gene knockout mice lacking CSD have significantly lower taurine concentrations than wild type controls, having a 90% reduction in hepatic taurine, and 70% reduction in renal taurine (Park E et al., Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Taurine Distribution in Various Tissues With and Without Taurine Supplementation. Adv Exp Med Biol. 2017;975 Pt 1 :461 -474).

2) The Fanconi Syndrome wastes small molecules including amino acids which are usually retained by the renal proximal tubules, further decreasing the availability of taurine.

Advantageously, by administering taurine and/or a prodrug thereof to subjects with cystinosis, taurine is able to correct mTOR signaling and is able to improve elements of cystinosis that have previously remain untreated by cysteamine. Therefore, taurine and/or a prodrug thereof provides an improved treatment for cystinosis.

Specifically, taurine is able to prevent renal failure in cystinosis patients. Taurine corrects increased autophagy, apoptosis, cytotoxicity and allows differentiation of proximal renal tubular cells, thus preventing renal failure in cystinosis patients. Taurine suppressed or attenuated increased autophagocytosis in three studies in three cell types (Sun et al., Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury. Aging (Albany NY); Liu et al., Regulation of taurine in OTA-induced apoptosis and autophagy. Toxicon. 2020 Jul 15; 181 :82-90.2020 Sep 15; 12(17): 17353-17366; Li et al., Taurine attenuates methamphetamine-induced autophagy and apoptosis in PC12 cells through mTOR signaling pathway. Toxicol Lett. 2012 Nov 23;215(1 ): 1 -7). Other factors improved by taurine include deficient myoblasts, vascular calcification, male infertility, and obesity.

Cystinotic tissues display cystine crystals which are known to produce inflammatory signals. Cystinosis cells express increased apoptosis. Taurine is able to decrease apoptosis and the amount of inflammatory signals as well as the amount of autophagy in cells exposed to calcium oxalate crystals. Studies in thirteen out of fourteen cell or tissue types showed taurine decreased, inhibited, or ameliorated apoptosis. In one study, free taurine did not decrease apoptosis, but apoptosis increased when the taurine transporter Tau(T) was knocked out (Tastesen, HS, et al. 2010. Pinpointing differences in cisplatin- induced apoptosis in adherent and non-adherent cancer cells. Cell Physiol Biochem 26, 809-820).

Even though cysteamine is a taurine precursor, dosage limitations due to cysteamine toxicity yield incomplete phenotypic correction. Addition of taurine and/or a prodrug thereof to the cysteamine treatment regimen for cystinosis will correct not only the cytosolic deficit of cysteine by allowing cystine to exit from the lysosomes, but correct via alternative pathways, the abnormalities of mTOR functions that result from mutant cystinosin.

A number of cystinosis genotypes are known, and some are specific for certain ethnicities [https://doi-org.proxy.lib.umich.edu/10.1159/000495270]. In some instances, taurine correction may be genotype-specific and molecular and biochemical testing will be required to determine correction and dose. In some embodiments, taurine and/or a prodrug thereof is co-administered with an effective amount of cysteamine. Advantageously, by administering cysteamine and taurine and/or a prodrug thereof, all elements of cystinosis are treated. Taurine is able to activate alternative pathways to the harmful state resulting from constitutive mTOR signaling, whilst cysteamine is able to reduce cystine accumulation in the lysosomes, resulting in an overall improved treatment of cystinosis.

In some embodiments, the effective amount of cysteamine is 10-30,000 mg of cysteamine (e.g., 10 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900mg, 1 ,000 mg, 10,000 mg, 20,000mg, 25,000 mg, 30,000 mg, or ranges therebetween (e.g., 50-90 mg of cysteamine, etc.), etc. In some embodiments, the effective amount of cysteamine is from about 25 to 30,000 mg/kg/day of cysteamine (e.g., 25 mg/kg/day, 500 mg/kg/day, 750 mg/kg/day, 1 ,000 mg/kg/day, 15,000 mg/kg/day, 20,000 mg/kg/day, 25,000 mg/kg/day, or ranges therebetween (e.g., 50-150 mg/kg/day, etc.)). In some embodiments, the effective amount of cysteamine does not exceed 30g/day (e.g., <2 g, <3 g, <4 g, <5 g, <6 g, <7 g, <8 g, <9 g, <30g). In some embodiments, the effective amount of cysteamine is 30g/day. In some embodiments, the effective amount of cysteamine is from about 50 to 90mg/kg/day.

Advantageously, by administering taurine and/or a prodrug thereof in accordance with the invention, a lower concentration of cysteamine may be required, which reduces the frequent, multiple doses of cysteamine currently required for treatment of cystinosis, and improves compliance with cysteamine.

Various cysteamine-related compounds may be co-administered with taurine and/or a prodrug thereof. Suitable cysteamine-related compounds for use in any embodiments herein include cysteamine, cystamine, phosphocysteamine, pharmaceutically acceptable salts thereof, all the hydrated forms of these compounds as well as the anhydrous forms. The term “cysteamine” as used herein refers to cysteamine, pharmaceutically acceptable salts thereof, as well as hydrated forms and anhydrous forms. The other cysteamine-related compounds described herein may also find use in any of the embodiments described herein. In this useage, cysteamine may be combined with vehicles which act to limit or counteract the smell and taste of cysteamine. Thus, in some embodiments, provided herein are methods for treating, preventing and/or ameliorating the symptoms of cystinosis in a subject by the administration of an effective amount of taurine and/or a prodrug thereof and an effective amount of cysteamine, cystamine, phosphocysteamine, or a pharmaceutically acceptable salt thereof.

Cysteamine may be prepared from ethanolamine and carbon disulfide via 2- mercaptothiazoline (Gabriel et al, Ber., vol. 31 , 2837 (1898); Knorr et al, Ber., vol. 36, 1281 (1903); and Mills, Jr. et al, J. Am. Chem. Soc., vol. 62, 1173 (1940)) or via ethyleneimine (Wenker, J. Am. Chem. Soc., vol. 57, 2328 (1935); Mills, Jr. et al, J. Am. Chem. Soc., vol. 62, 1173 (1940); and Shirley, Preparation of Organic Intermediates, Wiley, NY p. 189 (1951 ); incorporated by reference in their entireties).

Provided herein are supplements (e.g., comprising taurine and/or a prodrug thereof) and methods (e.g., administering taurine and/or a prodrug thereof or coadministering taurine and/or a prodrug thereof with additional therapies, such as cysteamine) for treating, preventing and/or ameliorating cystinosis, and symptoms/conditions arising therefrom (e.g., renal failure, etc.).

In some embodiments, taurine and/or a prodrug thereof is co-administered with an effective amount of cysteine. In some embodiments, taurine and/or a prodrug thereof is co-administered with an effective amount of cysteine and an effective amount of cysteamine. In some embodiments, taurine and/or a prodrug thereof is co-administered with an effective amount of cysteine and an effective amount of cysteamine orally.

In some embodiments, the effective amount of cysteine is 500-10,000 mg of cysteine (e.g., 500 mg, 600 mg, 700 mg, 800 mg, 900mg, 1 ,000 mg, 2,000 mg, 3,000 mg, 4,000 mg, 5,000 mg, 6,000 mg, 7,000 mg, 8,000 mg, 9,000 mg, 10,000 mg, or ranges therebetween (e.g., 500-900 mg of cysteine, etc.), etc. In some embodiments, the effective amount of cysteine is from about 500 to 10,000 mg/kg/day of cysteine (e.g., 500 mg/kg/day, 1 ,000 mg/kg/day, 2,000 mg/kg/day, 3,000 mg/kg/day, 4,000 mg/kg/day, 5,000 mg/kg/day, 10,000 mg/kg/day, or ranges therebetween (e.g., 500-700 mg/kg/day, etc.)).

In some embodiments, the effective dose (e.g., parenteral dose) comprises 10- 1 ,000 mg/kg/day of taurine (e.g., 100 mg/kg/day, 200 mg/kg/day, 300 mg/kg/day, 400 mg/kg/day, 500 mg/kg/day, 600 mg/kg/day, 800 mg/kg/day, or ranges therebetween (e.g., 250-650 mg/kg/day, etc.)). In some embodiments, the daily oral or intravenous dose does not exceed 20g/day of taurine (e.g., <2 g, <3 g, <4 g, <5 g, <6 g, <7 g, <8 g, <9 g, <20g. In some embodiments, the subject is first administered an initial dose (e.g., 25 mg/kg/day, 20 mg, etc.) and doses are subsequently increased (e.g., by 10 mg/kg/day, by 25 mg/dose, etc.) to an effective dose.

In some embodiments, a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

In some embodiments, a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

In some embodiments, a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

In some embodiments, the dose comprises 6,000-10,000 mg of taurine (e.g., 6,000mg, 6,500mg, 7,000mg, 7,500 mg, 8,000 mg, 8,500 mg, 9,000 mg, 9,500 mg, 10,000mg, or ranges therebetween (e.g., 7,250-8,750 mg of taurine, etc.), etc.

In some embodiments provided herein is the use of unit doses of taurine in the range of 2-20,000 mg, repeated at intervals (e.g., 6 hours, 12 hours, 24 hours, 48 hours, etc.) as required. In some embodiments, up to twenty doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or ranges there between) may be administered. In some embodiments, dose administration may be continued beyond 20 doses. In some embodiments, a maximum total dose/day is, for example, 2-20g (e.g., 2, g, 4, g, 6 g, 8 g, 10 g, 12 g, 14 g, 16 g, 18 g, 20 g, or more or ranges therebetween).

In some embodiments, taurine is provided in 2-20,000 mg doses (e.g., 2 mg, 1 ,000 mg, 1 ,500mg, 2,000, 2,500 mg, 3,000 mg, 3,500 mg, 4,000 mg, 4,500 mg, 5,000 mg,

5.500 mg, 6,000 mg, 6,500 mg, 7,000mg, 7,500 mg, 8,000 mg, 8,500 mg, 9,000 mg,

9.500 mg, 10,000 mg, 10,500 mg, 11 ,000 mg, 11 ,500mg, 12,000, 12,500 mg, 13,000 mg,

13.500 mg, 14,000 mg, 14,500 mg, 15,000 mg, 15,500 mg, 16,000 mg, 16,500 mg, 17,000mg, 17,500 mg, 18,000 mg, 18,500 mg, 19,000 mg, 19,500 m 20,000 mg, and ranges therebetween (e.g., 50-150 mg)). In some embodiments, taurine is provided in 50- 300mg/kg body wt doses. The skilled person would be able to determine an appropriate dose of prodrug to be administered based on the amount of taurine required. For example, if 6,000-10,000 mg of taurine is required, the skilled person can readily determine a dosage of prodrug to be administered that would metabolize to 6,000-10,000 mg of taurine.

In some embodiments, the subject is first administered an initial dose of taurine and/or a prodrug thereof and doses are subsequently increased to the effective amount. In some embodiments, the effective amount is from about 10 to 1 ,000m g/kg/day of taurine. In some embodiments, the effective amount does not exceed 20g/day of taurine. In some embodiments, the dose is adjusted based on the effectiveness and/or side effects of initial dosing. For example, if the initial dose is/appears effective and/or side effects are/appear significant, the dose may be reduced (e.g., 10-500 mg (e.g., 100 mg, 200 mg, 30 mg, 400 mg, 500mg, and ranges there between (e.g., 30-50 mg)). If the initial dose is/appears ineffective and/or side effects are/appear insignificant, the dose may be increased. In some embodiments, an initial dose of taurine and/or a prodrug thereof is provided and ramped up to a final dose with increments of, for example, 10mg/kg/d at intervals (e.g., 2 week intervals).

In some embodiments, taurine and/or a prodrug thereof is administered daily, twice daily, thrice daily, on alternate days, etc. In some embodiments, taurine and/or a prodrug thereof is administered (e.g., daily, twice daily, thrice daily, on alternate days, weekly, etc.) for a set time span (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, or more), of until symptoms or testing demonstrate the effectiveness of the treatment.

Advantageously, because taurine is a naturally occurring amino acid, a higher concentration of taurine and/or a prodrug thereof can be administered, which means fewer doses throughout a patient’s lifespan.

In some embodiments, dosing is guided by laboratory and/or clinical studies.

In some embodiments, taurine and/or a prodrug thereof is administered orally.

In some embodiments, taurine and/or a prodrug thereof is administered intravenously. In some embodiments, taurine and/or a prodrug thereof is administered enterally, parenterally, or by any suitable route of administration.

In some embodiments, taurine and/or a prodrug thereof is administered to the eye. In a preferred embodiment, taurine and/or a prodrug thereof is co-administered with cysteamine to the eye. In addition to other tissues affected by taurine, the eye has been found to have impaired taurine metabolism. It appears the retina is set to produce taurine as CSD (cysteinesulfinate decarboxylase) immunoreactivity was seen in every layer of the eye. The salt and pepper retinopathy in eyes of subjects with cystinosis is one of the first clinical manifestations to appear and which is not universally responsive to cysteamine. The retinopathy may be the result of taurine deficiency. Advantageously, by administering taurine and/or a prodrug thereof, the retinopathy displayed in subjects with cystinosis may be treated.

In some embodiments, taurine and/or a prodrug thereof is administered enterally e.g. by oral administration, rectal administration, administration using a nasogastric tube, nasointestinal tube, percutaneous endoscopic gastrostomy tube etc. In a preferred embodiment, taurine is administered orally. In some embodiments, taurine and/or a prodrug thereof is co-administered with cysteamine orally.

In some embodiments, taurine and/or a prodrug thereof is administered parenterally e.g. by injection (e.g., intravenous, intramuscular, subcutaneous, intrathecal), sublingual administration (under the tongue), inhalation (into bronchi) etc. In a preferred embodiment, taurine and/or a prodrug thereof is administered by injection (e.g. intravenously). In some embodiments, taurine and/or a prodrug thereof is coadministered with cysteamine by injection.

Taurine and/or a prodrug thereof can be administered intrabronchially, e.g. by way of bronchial inhaler, or other means. In some embodiments, taurine and/or a prodrug thereof is formulated as a liquid or micronized powder, which permit achieving very high intra-bronchial concentrations.

In some embodiments, the taurine and/or a prodrug thereof is administered in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament. In a preferred embodiment, taurine and/or a prodrug thereof is co-administered with cysteamine in the form of a dietary supplement.

The invention also provides a supplement for cystinosis comprising taurine and/or a prodrug thereof, wherein the supplement is formulated for administration to a subject. In some embodiments, the supplement is in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament. In a preferred embodiment, a medication for cystinosis comprising taurine and cysteamine is formulated for administration to a subject.

In some embodiments, a supplement for cystinosis is administered enterally and/or parenterally to a subject, wherein the supplement comprises taurine and/or a prodrug thereof.

The supplement described herein may be used as (or used as part of) a dietary supplement, a nutraceutical, a food composition, a medical food, or a medicament.

The term "dietary supplement" or "food supplement" as used herein, refers to a supplement which is consumed in addition to the daily meals or in between. The term "food supplement" as used herein, refers to any kind of composition which is eatable and/or drinkable without causing toxic symptoms in the subject eating or drinking the respective composition.

In some embodiments, the supplements and/or methods herein find use in treatment, prevention and/or amelioration of cystinosis, conditions, or symptoms arising therefrom. In some embodiments, taurine and/or a prodrug thereof is administered intravenously and/or orally (alone or co-administered with other agents, including but not limited to cysteamine) for the treatment, prevention and/or amelioration of cystinosis, conditions, or symptoms arising therefrom.

In some embodiments, methods are provided for treating, preventing and/or ameliorating cystinosis by the co-administration of taurine and/or a prodrug thereof with one or more additional therapeutics or therapies.

In some embodiments, the taurine and/or a prodrug thereof is co-administered with one or more additional therapeutics.

In some embodiments, the subject has failed treatment with cysteamine. Unfortunately, the structure of cysteamine includes a free thiol group, thus the drug has the odor and taste of rotten eggs, a feature of concern both to parents administering the treatment to children, and to subjects themselves who may find the offensive odor to be socially debilitating. Due to the repugnant odor and taste, cysteamine can trigger chemoreceptors in subjects causing them to vomit. Subjects are more likely to vomit when cysteamine is administered if the subject is under 18 years old. In some embodiments, taurine and/or a prodrug thereof is administered to a subject is under 18 years old. In some embodiments, the subject is 6 months to 16 years old. In some embodiments, the subject is between 6 months to 10 years old. In some embodiments, the subject is 2 months to 16 years old. In some embodiments, the subject is between 2 months to 10 years old. A subject who has failed treatment with cysteamine refers to a subject who either voluntarily or involuntary cannot be administered with cysteamine. In particular, a subject has failed treatment with cysteamine if the subject vomits when cysteamine is administered. In some embodiments, the subject is first administered an initial dose of cysteamine. If the subject fails treatment with cysteamine i.e. because cysteamine causes the subject to vomit, the subject is administered a subsequent dose of taurine and/or a prodrug thereof.

Advantageously, taurine is a naturally occurring amino acid and therefore does not have a repugnant odor and taste. Taurine and/or a prodrug thereof has an improved taste compared to cysteamine, resulting in an overall improved treatment for subjects with cystinosis. Taurine and/or a prodrug thereof can be administered in higher doses without the increased risk of subjects vomiting or rejecting the treatment due to the lack of repugnant odor and/or taste. This means taurine and/or a prodrug thereof can be administered in a higher concentration resulting in fewer doses throughout a patient’s lifespan.

In some embodiments, taurine and/or a prodrug thereof is co-administered with an effective amount of cysteamine. Advantageously, by administering taurine and/or a prodrug thereof in accordance with the invention, taurine and/or a prodrug thereof is able to reduce the repugnant odor and taste of cysteamine by reducing the required dose of cysteamine. Therefore, subjects who previously failed treatment with cysteamine, may be able to tolerate cysteamine and taurine and/or a prodrug thereof.

The invention contemplates combinations of any of the foregoing aspects and embodiments of the invention. Each and every embodiment described throughout the application can be combined, and can be applied to each and every aspect of the invention described herein. Further, the methods and reagents of the various aspects of the instant invention can be used prophylactical ly. Alternatively, they can be used therapeutically. The invention can be described with reference to the following numbered paragraphs:

Paragraph 1 . A method of treating, preventing and/or ameliorating cystinosis in a subject, the method comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

Paragraph 2. The method of paragraph 1 , wherein the taurine and/or prodrug thereof is co-administered with an effective amount of cysteamine.

Paragraph 3. The method of any one of paragraph 1 or paragraph 2, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

Paragraph 4. The method of any one of paragraphs 1-3, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

Paragraph 5. The method of any one of paragraphs 1-4, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

Paragraph 6. The method of any one of paragraphs 1-5, wherein the taurine and/or a prodrug thereof is administered daily.

Paragraph 7. The method of any one of paragraphs 1 -6, wherein the taurine and/or a prodrug thereof is administered twice daily.

Paragraph 8. The method of any one of paragraphs 1 -7, wherein taurine and/or a prodrug thereof is administered orally.

Paragraph 9. The method of any one of paragraphs 1 -8, wherein the taurine and/or a prodrug thereof is administered intravenously.

Paragraph 10. The method of any one of paragraphs 1-9, wherein the effective amount is from about 10 to 1 ,000 mg/kg/day of taurine.

Paragraph 11 . The method of paragraph 10, wherein the effective amount does not exceed 20g/day of taurine. Paragraph 12. The method of any one of paragraphs 1-11 , wherein the subject is first administered an initial dose of taurine and/or a prodrug thereof and doses are subsequently increased to the effective amount.

Paragraph 13. The method of any one of paragraphs 1-12, wherein the taurine and/or a prodrug thereof is administered in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament.

Paragraph 14. The method of any one of paragraphs 1-13, wherein the taurine and/or a prodrug thereof is co-administered with one or more additional therapeutics.

Paragraph 15. The method of any one of paragraphs 1-14, wherein the subject is under 18 years old.

Paragraph 16. The method of any one of paragraphs 1 -15, wherein the subject has failed treatment with cysteamine.

Paragraph 17. Use of an effective amount of taurine and/or a prodrug thereof administered for treating, preventing and/or ameliorating cystinosis in a subject.

Paragraph 18. The use of paragraph 17, wherein the taurine and/or a prodrug thereof is co-administered with cysteamine.

Paragraph 19. The use of paragraph 17 or paragraph 18, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

Paragraph 20. The use of any one of paragraphs 17-19, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

Paragraph 21. The use of any one of paragraphs 17-20, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

Paragraph 22. The use of any one of paragraphs 17-21 , wherein the subject is under 18 years old.

Paragraph 23. The use of any one of paragraphs 17-22, wherein the subject has failed treatment with cysteamine. Paragraph 24. Taurine and/or a prodrug thereof for use in treating, preventing and/or ameliorating cystinosis in a subject, wherein the taurine and/or a prodrug thereof is administered to the subject in an effective amount.

Paragraph 25. The taurine and/or a prodrug thereof for use according to paragraph 24, wherein the taurine and/or a prodrug thereof is co-administered with cysteamine.

Paragraph 26. The taurine and/or a prodrug thereof for use according to paragraph 24 or paragraph 25, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

Paragraph 27. The taurine and/or a prodrug thereof for use according to any one of paragraphs 24-26, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

Paragraph 28. The taurine and/or a prodrug thereof for use according to any one of paragraphs 24-27, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

Paragraph 29. The taurine and/or a prodrug thereof for use according to any one of paragraphs 24-28, wherein the subject is under 18 years old.

Paragraph 30. The taurine and/or a prodrug thereof for use according to any one of paragraphs 24-29, wherein the subject has failed treatment with cysteamine.

Paragraph 31. A supplement for cystinosis comprising taurine and/or a prodrug thereof, wherein the supplement is formulated for administration to a subject.

Paragraph 32. The supplement of paragraph 31 , wherein the taurine and/or a prodrug thereof is co-administered with cysteamine.

Paragraph 33. The supplement of paragraph 31 or paragraph 32, wherein the supplement is in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament. Paragraph 34. The supplement of any one of paragraphs 31-33, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

Paragraph 35. The supplement of any one of paragraphs 31 -34, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

Paragraph 36. The supplement of any one of paragraphs 31-35, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

Paragraph 37. The supplement of any one of paragraphs 31 -36, wherein the subject is under 18 years old.

Paragraph 38. The supplement of any one of paragraphs 31 -37, wherein the subject has failed treatment with cysteamine.

Claims

1 . A method of treating, preventing and/or ameliorating cystinosis in a subject, the method comprising administering an effective amount of taurine and/or a prodrug thereof to the subject.

2. The method of claim 1 , wherein the taurine and/or prodrug thereof is coadministered with an effective amount of cysteamine.

3. The method of claim 1 , wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

4. The method of claim 1 , wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

5. The method of claim 1 , wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

6. The method of claim 1 , wherein the taurine and/or a prodrug thereof is administered daily.

7. The method of claim 1 , wherein the taurine and/or a prodrug thereof is administered twice daily.

8. The method of claim 1 , wherein taurine and/or a prodrug thereof is administered orally.

9. The method of claim 1 , wherein the taurine and/or a prodrug thereof is administered intravenously.

10. The method of claim 1 , wherein the effective amount is from about 10 to 1 ,000 mg/kg/day of taurine.

11 . The method of claim 10, wherein the effective amount does not exceed 20g/day of taurine.

12. The method of claim 1 , wherein the subject is first administered an initial dose of taurine and/or a prodrug thereof and doses are subsequently increased to the effective amount.

13. The method of claim 1 , wherein the taurine and/or a prodrug thereof is administered in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament.

14. The method of claim 1 , wherein the taurine and/or a prodrug thereof is coadministered with one or more additional therapeutics.

15. The method of claim 1 , wherein the subject is under 18 years old.

16. The method of claim 1 , wherein the subject has failed treatment with cysteamine.

17. Use of an effective amount of taurine and/or a prodrug thereof administered for treating, preventing and/or ameliorating cystinosis in a subject.

18. The use of claim 17, wherein the taurine and/or a prodrug thereof is coadministered with cysteamine.

19. The use of claim 17, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

20. The use of claim 17, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

21. The use of claim 17, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

22. The use of claim 17, wherein the subject is under 18 years old.

23. The use of claim 17, wherein the subject has failed treatment with cysteamine.

24. Taurine and/or a prodrug thereof for use in treating, preventing and/or ameliorating cystinosis in a subject, wherein the taurine and/or a prodrug thereof is administered to the subject in an effective amount.

25. The taurine and/or a prodrug thereof for use according to claim 24, wherein the taurine and/or a prodrug thereof is co-administered with cysteamine.

26. The taurine and/or a prodrug thereof for use according to claim 24, wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

27. The taurine and/or a prodrug thereof for use according to claim 24, wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

28. The taurine and/or a prodrug thereof for use according to claim 24, wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

29. The taurine and/or a prodrug thereof for use according to claim 24, wherein the subject is under 18 years old.

30. The taurine and/or a prodrug thereof for use according to claim 24, wherein the subject has failed treatment with cysteamine.

31. A supplement for cystinosis comprising taurine and/or a prodrug thereof, wherein the supplement is formulated for administration to a subject.

32. The supplement of claim 31 , wherein the taurine and/or a prodrug thereof is coadministered with cysteamine.

33. The supplement of claim 31 , wherein the supplement is in the form of a dietary supplement, a nutraceutical, a food composition, a medical food, beverage or a medicament.

34. The supplement of claim 31 , wherein a dose of from about 2 mg to about 20,000mg of taurine is administered to the subject.

35. The supplement of claim 31 , wherein a dose of from about 5,000 mg to about 20,000 mg of taurine is administered to the subject.

36. The supplement of claim 31 , wherein a dose of from about 6,000 mg to about 10,000 mg of taurine is administered to the subject.

37. The supplement of claim 31 , wherein the subject is under 18 years old.

38. The supplement of claim 31 , wherein the subject has failed treatment with cysteamine.