Pharmaceutical composition for lysosomal storage disorder and use thereof

Abstract

To provide improved methods for treating lysosomal storage disorders (LSDs).SOLUTION: The present invention provides acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of treating a lysosomal storage disorder (LSD) or one or more symptoms associated with a LSD in a subject in need thereof, wherein the LSD is not Niemann-Pick Type C.SELECTED DRAWING: Figure 9A

Description

[Technical Field]

[0001] This application claims priority to UK1613828.1 filed August 11, 2016, UK1702552.9 filed February 16, 2017, UK1705762.1 filed April 10, 2017, and UK1706854.5 filed April 28, 2017, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Lysosomal storage disorders (LSDs) are inherited metabolic disorders caused by defects in lysosomal homeostasis. To date, with a collective clinical frequency of 1:5000 live births, LSDs encompass more than 70 disorders. These disorders can be classified into two main groups: primary storage disorders (typically lysosomal enzyme deficiency disorders) resulting from direct deficiencies in degradative pathways, and secondary storage disorders (e.g., defects in trafficking pathways) caused by processes affecting lysosomes or dysfunctional downstream lysosomal proteins.

[0003] LSD (LSDs) pathology affects many of the body's systems, but most commonly affects the nervous system. Progressive neurodegeneration resulting in physical disability and mental deterioration is a common symptom. Such disorders are generally severely progressive and relentless. They tend to appear during the first few years of life, and severe progression results in frequent hospitalization. If left untreated, patients often die in their mid-teens. Adult-onset cases have also been described. Summary of the Invention [Problem to be solved by the invention]

[0004] Current treatment approaches for LSDs are limited. Few, if any, curative treatments are available, and many of the treatment options merely improve quality of life. For example, some LSDs have responded to bone marrow transplantation or enzyme replacement therapy. In addition, some benefit has been reported in clinical trials of substrate reduction therapy (SRT) using the glycosphingolipid (GSL) biosynthesis inhibitor miglustat, an iminosugar drug (Patterson, 2006). However, there is currently no general, nonspecific treatment that benefits all LSDs. Therefore, there is a need to develop improved treatments for LSDs.

[0005] The present disclosure addresses this need and describes acetyl-leucine for treating LSD or one or more symptoms of LSD in a subject in need thereof.

[0006] In one embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of treating LSD or one or more symptoms associated with LSD in a subject in need thereof, wherein the LSD is not Niemann-Pick Type C.

[0007] In one embodiment of the present disclosure, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of treating LSD in a subject in need thereof, wherein the subject is asymptomatic.

[0008] In another embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of delaying the onset of LSD or one or more symptoms of LSD that would otherwise be predicted to appear according to a typical disease progression.

[0009] In further embodiments, the disclosure includes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of treating LSD or one or more symptoms associated with LSD, wherein the method comprises administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[0010] In one embodiment, the present disclosure describes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for delaying the progression of LSD or one or more symptoms associated with LSD relative to typical disease progression, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 2 years, and at least about 5 years.

[0011] In further embodiments, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method for reversing the progression of LSD or one or more symptoms associated with LSD over time, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[0012] In another embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of improving biochemical markers of LSD over time in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[0013] In another embodiment, the disclosure includes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of reducing the severity of LSD, or reducing or eliminating the severity of one or more existing symptoms associated with LSD, in a subject in need thereof, wherein the LSD is not Niemann-Pick disease type C.

[0014] In further embodiments, the present disclosure includes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of providing neuroprotection in a subject having, suspected of having, or at risk of having LSD, wherein the method comprises administering a therapeutically effective amount of acetyl-leucine to the subject for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[0015] Further examples of the present disclosure include acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method for delaying the progression of lysosomal storage disorder (LSD) in a subject. Also, acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method for providing neuroprotection in a subject with LSD. The acetyl-leucine is in the form of a racemate in enantiomeric excess of the L-enantiomer. The method further includes administering acetyl-leucine at a dose of between 1.5 g and 10 g per day. Furthermore, the method includes administering acetyl-leucine for a treatment period of two weeks or more. The method may also include administering acetyl-leucine or a pharmaceutically acceptable salt thereof prior to the onset of symptoms of LSD. The method may further include administering another therapy or agent aimed at preventing or treating LSD. A further embodiment of the present disclosure is a kit for delaying the progression of LSD in a subject, the kit comprising a means for diagnosing or prognosing LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof. The kit comprises a means for diagnosing or prognosing LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof. Yet another embodiment of the present disclosure is the use of acetyl-leucine or a pharmaceutically acceptable salt thereof as a neuroprotective agent in a subject with LSD.In further embodiments of the above-mentioned methods, kits, or uses, the LSD is Niemann-Pick disease type C (NPC1 and / or NPC2 deficiency), Smith-Lemli-Opitz syndrome (SLOS), an inborn error of cholesterol synthesis, Tangier disease, Pelizaeus-Merzbacher disease, neuronal ceroid lipofuscinosis, primary glycosphingolipidosis, Farber disease, or multiple sulfatase deficiency. Additionally, in another embodiment of the method, kit, or use, the primary glycosphingolipidosis is Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease, or metachromatic leukodystrophy (MLD). In a further embodiment of the method, kit or use, the LSD is NPC, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, Fabry disease, neurodegenerative mucopolysaccharidosis, MPS I, MPS IH, MPS IS, MPS II, MPS III, MPS IIIA, MPS IIIB, MPS IIIC, MPS HID, MPS, MPS IV A, MPS IV B, MPS VI, MPS VII, MPS IX, secondary lysosomal involvement disease, SLOS, or Tangier disease.In another embodiment of the method, kit, or use, the LSD is Niemann Pick disease, Niemann Pick type C, Niemann Pick type A, Sandhoff's disease, Tay-Sachs disease, or mucolipidosis type II.

[0016] These and other embodiments and features of the present disclosure will become apparent from the following description and claims. [Brief explanation of the drawings]

[0017] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows photographs of treated (FIG. 1A) and untreated (FIG. 1B) Npc1 − / − mice at 9 weeks of age.

[0018] [Figure 2] Figures 2A and 2B show body weight data for Npc1- / - mice compared to wild-type (Npc1+ / +) mice, with and without acetyl-DL-leucine treatment, from weaning.

[0019] [Figure 3]Figures 3A-G show gait analysis data for Npc1- / - mice compared with wild-type (Npc1+ / +) mice, with and without acetyl-DL-leucine treatment, from weaning. For example, diagonal support, cadence, and step sequence data are shown in Figures 3A-C, respectively. Figures 3D and 3E show front paw (FP) data (stand mean and step cycle in panel D; duty cycle in panel E). Figures 3F and 3G show hind paw (HP) data (stand mean and step cycle in panel F; duty cycle in panel G).

[0020] [Figure 4] Figures 4A–H show motor function analysis data from Npc1– / – mice compared with wild-type (Npc1+ / +) mice, with and without acetyl-DL-leucine treatment, from weaning. Figures 4A–4D show center rearing, activity, rearing, and front-to-back (FR) counts, respectively. Figures 4E–4H show active time, mobile time, rearing time, and total manual rearing counts, respectively.

[0021] [Figure 5]FIG. 5 shows that treatment with acetyl-DL-leucine (0.1 g / kg from 3 weeks of age) is associated with a small but statistically significant increase in lifespan in Npc1 − / − mice.

[0022] [Figure 6] Figures 6A and 6B show the reduction in lysosomal mass in non-neuronal NPC cells following treatment with acetyl-DL-leucine. Figures 6C-6H show the effect of acetyl-DL-leucine treatment on lysosomal mass in fibroblasts from NPA, MLII, MPS IIIB, aspartylglucosaminuria, MLIIIA, and MPS VII patients, respectively.

[0023] [Figure 7] Figure 7A shows survival curves representing mortality in untreated or acetyl-leucine-treated wild-type and Sandhoff mice. Figure 7B shows bar crossing scores for untreated and acetyl-leucine-treated Sandhoff model mice. Figure 7C shows step cycle times for untreated and acetyl-leucine-treated Sandhoff mice evaluated at 12 weeks of age.

[0024] [Figure 8] Figures 8A-8C show the effect of acetyl-DL-leucine treatment on glycosphingolipid (GSL) levels in fibroblasts from patients with GM2 gangliosidoses (Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease, respectively).

[0025] [Figure 9] Figures 9A and 9B show the effect of treatment with acetyl-DL-leucine over time on the overall clinical severity score (CSS) and overall annual severity increment score (ASIS), respectively, of 10 NPC patients.

[0026] [Figure 10] Figures 10A-10J show the effect of treatment with acetyl-DL-leucine on CSS subscores over time for each of the 10 NPC patients. DETAILED DESCRIPTION OF THE INVENTION

[0027] [Description] Acetyl-leucine (acetyl-DL-leucine) in the form of the racemate and its salts are effective in treating vertigo of various origins, particularly that of Meniere's disease and vertigo of inflammatory (vestibular neuritis) or toxic origin. For example, acetyl-leucine is marketed in the form of the racemate by Pierre Fabre Medicament as an antivertigo drug under the trade name Tanganil®. Clinical results with Tanganil® reported by various authors show improvement in vertigo symptoms in more than 95% of cases, including the disappearance of vertigo attacks.

[0028] Acetyl-DL-leucine has been used to treat acute vertigo in France since 1957 and has an excellent safety profile, but its safety in chronic use has not been determined. Its pharmacological and electrophysiological mode of action remains unclear, despite numerous hypotheses, including stabilization of membrane potential. (Vibert et al. (2001) Eur J Neurosci;13(4):735-48; Ferber-Viart et al. (2009) Audiol Neurootol;14(1):17-25) An FDG-μPET study in a rat model of acute unilateral labyrinthectomy (Zwergal et al. (2016) Brain Struct Funct;221(1):159-70) showed a significant effect of the L-enantiomer, N-acetyl-L-leucine, on postural compensation by inactivating the posterolateral thalamus and activating the vestibulocerebellum (Gunther et al. (2015) PLoS One;10(3):e0120891). Improvement of cerebellar ataxia symptoms with acetyl-DL-leucine was shown in a case series involving cerebellar patients (Strupp et al. (2013) J Neurol;260(10):2556-61). Another case series found no benefit (Pelz et al. (2015) J Neurol;262(5):1373-5). Quantitative gait analysis (gait analysis) showed that acetyl-DL-leucine improved transient gait variability in patients with cerebellar ataxia (Schniepp et al. (2015) Cerebellum;3:8). A 1-month study including 12 patients with Niemann-Pick disease type C (NPC) showed improvement in ataxia symptoms (Bremova et al. (2015) Neurology;85(16):1368-75).Furthermore, PET studies in patients with ataxia given acetyl-DL-leucine showed increased metabolism in the midbrain and lower brainstem in responders (Becker-Bense et al. (2015) Abstract EAN).

[0029] However, acetyl-leucine is not known to treat LSDs, which generally progress over years to decades. The present disclosure surprisingly demonstrates that acetyl-leucine, or a pharmaceutically acceptable salt thereof, can be used in methods of treating LSDs in a subject in need thereof by slowing or reversing the progression of LSD or one or more symptoms of LSD, e.g., over a prolonged period compared to typical disease progression, and / or by delaying the onset of LSD or one or more symptoms of LSD that would otherwise be expected to manifest with typical disease progression. These exemplary uses according to the present disclosure, and others described herein, were entirely unexpected; such benefits were not observed and could not be deduced from the teachings of the prior art. LSDs are a group of various genetic disorders often characterized by the accumulation of undigested or partially digested macromolecules, resulting in cellular dysfunction (e.g., increased lysosomal mass compared to healthy subjects) and clinical abnormalities. Without wishing to be bound by any particular theory, the inventors have discovered, as evidenced by experimental examples, that acetyl-leucine can improve cellular dysfunction (e.g., by reducing lysosomal mass toward control values) and clinical abnormalities, particularly in subjects suffering from LSD.

[0030] Accordingly, the present disclosure provides acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of treating LSD or one or more symptoms of LSD in a subject in need thereof.

[0031] As used herein, "LSD" refers to any disorder involving dysfunction or disruption in the late endosomal / lysosomal system and the accumulation of undigested or partially digested large macromolecules. LSD may include increased storage of lipid or non-lipid molecules.

[0032] As used herein, a "subject" may be a vertebrate, mammal, or livestock. Thus, compositions according to the present disclosure may be used to treat any mammal, such as livestock (e.g., horses, cows, sheep, or pigs), pets (e.g., cats, dogs, rabbits, or guinea pigs), laboratory animals (e.g., mice or rats), or other veterinary applications. For example, the subject may be a human.

[0033] As used herein, the singular forms "a," "an," and "the" include plural references.

[0034] The terms "approximately" and "about" mean approximately the same as a referenced number or value, including an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. As used herein, the terms "approximately" and "about" should generally be understood to encompass ±20% of the specified quantity, frequency, or value. Numerical quantities given herein are approximations unless otherwise stated, meaning that the term "about" or "approximately" can be inferred when not expressly stated.

[0035] As used herein, the terms "administer," "administration," or "administering" mean (1) providing, giving, administering, and / or prescribing a composition according to the present disclosure by or under the direction of a medical practitioner or his authorized agent, and (2) ingesting, taking, or consuming a composition according to the present disclosure by a patient or oneself.

[0036] Unless expressly stated, references throughout to "acetyl-leucine" include pharmaceutically acceptable salts thereof.

[0037] Acetyl-leucine may be in the form of a racemate, which means that the compound contains approximately equal amounts of enantiomers. Alternatively, the compound may be present in enantiomeric excess of either the L-enantiomer or the D-enantiomer. Acetyl-leucine may be in the form of a single enantiomer, either the L-enantiomer or the D-enantiomer. In one embodiment, the single enantiomer is the L-enantiomer. Racemic and enantiomeric forms may be obtained according to procedures known in the art.

[0038] As referred to herein, "pharmaceutically acceptable salts" refers to any salt preparation suitable for use in pharmaceutical applications. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine, and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chloro-benzyl-2-pyrrolidin-1'-ylmethylbenzimidazole ... alkali metal salts such as lithium, potassium, sodium, etc.; alkaline earth metal salts such as barium, calcium, magnesium, etc.; transition metal salts such as zinc, aluminum, etc.; other metal salts such as sodium hydrogen phosphate, disodium phosphate, etc.; mineral acids such as hydrochlorides, sulfates, etc.; salts of organic acids such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate, etc.

[0039] Acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated and administered to a subject according to teachings known in the art. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated as a pharmaceutical composition. The pharmaceutical composition may include acetyl-leucine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Reference to a pharmaceutical composition includes an active agent, either alone or in the form of a pharmaceutical composition.

[0040] A pharmaceutical composition may take any of a number of different forms, depending in particular on the manner in which it is to be used. Thus, for example, it may be a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposomal suspension, or another form appropriate for administration to a human or animal in need of treatment.

[0041] The "pharmaceutically acceptable carrier" referred to herein is any known compound or combination of known compounds known to those skilled in the art to be useful in formulating pharmaceutical compositions. It will be understood that a carrier for a pharmaceutical composition should be one that can be tolerated by the subject to which it is given.

[0042] In one embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in powder or tablet form. Solid pharmaceutically acceptable carriers may include one or more substances which may also function, but are not limited to, flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coating agents, or tablet disintegrating agents. The carrier may also be an encapsulating material. In powders, the carrier may be a finely divided solid mixed with the finely divided active agent of the present invention. In tablets, the active agent may be mixed with a carrier having the necessary compression properties in appropriate proportions and compacted into the desired shape and size. Powders and tablets may contain, for example, up to 99% of the active agent. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins, hi another example, the pharmaceutically acceptable carrier may be a gel and the composition may be in the form of a cream or the like.

[0043] A carrier may include, but is not limited to, one or more excipients or diluents, examples of which include gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.

[0044] In another embodiment, the pharmaceutically acceptable carrier may be liquid. In one embodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. Acetyl-leucine may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable excipients such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity adjusters, stabilizers, or osmolality adjusters. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing an excipient such as a cellulose derivative, e.g., sodium carboxymethylcellulose solution), alcohols (including polyhydric alcohols and monohydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, carriers may also be oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. Liquid carriers for pressurized compositions may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0045] Liquid pharmaceutical compositions that are sterile solutions or suspensions may be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and particularly subcutaneous injection. The active agent may also be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.

[0046] The compositions may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleic acid ester of sorbitol and its anhydride copolymerized with ethylene oxide), etc. The compositions may also be administered orally in either liquid or solid composition form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders, and liquid forms such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0047] Acetyl-leucine and compositions containing it may alternatively be administered by inhalation (e.g., intranasally). Compositions may also be formulated for topical use. For example, a cream or ointment may be applied to the skin.

[0048] Acetyl-leucine may be incorporated into a sustained-release or delayed-release device. Such a device may, for example, be inserted on or under the skin, and the drug may be released over a period of weeks or months. Such a device may be advantageous when long-term treatment with acetyl-leucine used in accordance with the present disclosure is required and when frequent administration (e.g., at least daily) is typically required.

[0049] In one embodiment, the pharmaceutical composition is in the form of a tablet. In tablets, the active agent may be mixed in suitable proportions with a vehicle, such as a pharmaceutically acceptable carrier, having the necessary compression properties and compressed into the desired shape and size. Tablets may contain up to 99% by weight of the active agent.

[0050] For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be provided in a solid dosage form suitable for oral administration, particularly in the form of a tablet.

[0051] Pharmaceutical compositions in solid oral dosage forms such as tablets may be prepared by any method known in the art of pharmacy, and are typically prepared by mixing acetyl-leucine or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier.

[0052] Tablets may be formulated as known in the art. Tanganil®, for example, contains wheat starch, pregelatinized maize (corn) starch, calcium carbonate, and magnesium stearate as excipients. For example, the same or similar excipients may be used with the present disclosure.

[0053] Each 700 mg Tanganil® tablet has the following composition: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinized maize (corn) starch, 13 mg calcium carbonate, and 11 mg magnesium stearate. For example, the same tablets may be used with the present disclosure.

[0054] The present disclosure describes acetyl-leucine containing compositions and methods for treating LSD or one or more symptoms of LSD in a subject in need thereof. A subject in need thereof may have a genetic, biochemical, or other similar identifiable marker for LSD. For example, the marker for LSD may be a cellular marker. A subject in need thereof may have been diagnosed with LSD. For example, the subject may have been diagnosed with LSD according to a genetic, biochemical, or other similar identifiable marker. A subject in need thereof may be suspected of having or at risk of having LSD. For example, the subject may have a genetic predisposition to LSD (e.g., the subject may have one or more family members with LSD). A subject in need thereof may be symptomatic (i.e., have one or more symptoms associated with LSD). A subject in need thereof may be asymptomatic. It should be understood that the terms "symptomatic" and "asymptomatic" are used with reference to the symptoms of LSD. Subjects who have genetic, biochemical, or other similar identifiable markers of an LSD are included within the scope of "asymptomatic" for purposes of this disclosure, such as subjects who have been diagnosed with an LSD based on genetic, biochemical, or other similar identifiable markers, but who have no further symptoms of the disease.

[0055] As used herein, "treating LSD or one or more symptoms of LSD" and the like means delaying the onset of LSD or one or more symptoms of LSD that would otherwise be expected to develop according to a typical disease progression, reducing the severity of LSD over time or reducing or eliminating the severity of one or more existing symptoms associated with LSD, slowing the progression of LSD or the progression of one or more symptoms of LSD over time compared to a typical disease progression, and / or reversing the progression of LSD or one or more symptoms of LSD over time. "Treating LSD or one or more symptoms of LSD" can also mean improving biochemical markers of LSD.

[0056] As used herein, "typical disease progression," "typically expected disease progression," and the like refer to the typical or expected progression of an LSD, one or more symptoms associated with an LSD, or, if the subject is not treated, a biochemical marker of an LSD. Typical or expected disease progression may be based, for example, on a known scale, index, rating, or score, or other suitable test, for assessing the progression of an LSD, one or more symptoms associated with an LSD, or a biochemical marker of an LSD. The scale, index, rating, score, or other suitable test may correspond to the progression of an LSD overall or the progression of one or more symptoms associated with an LSD. For example, typical or expected disease progression may be based on the typical or expected onset or severity of an LSD, or a symptom or set of symptoms associated with an LSD. Typical or expected disease progression may be determined for each subject, or may be based on that typically experienced by or observed for a population of subjects suffering from an LSD, such as a population or subpopulation of subjects. The subpopulations may include, for example, subpopulations of the same sex, of the same or similar age, of the same or similar timing for onset of one or more symptoms, and so on.

[0057] In one embodiment, "treating LSD or one or more symptoms of LSD" means delaying the onset of LSD or one or more symptoms of LSD that would otherwise be expected to occur according to a typical disease progression. As used herein, "delaying the onset of LSD or one or more symptoms of LSD" and the like means extending the time to onset of, or preventing the onset of, LSD or one or more symptoms of LSD. For example, onset can be said to be delayed when the time to onset of LSD or one or more symptoms of LSD is at least 5% longer than observed according to a typical disease progression. Further, for example, an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% is observed. In one embodiment, the subject is asymptomatic (symptom-free). Administration of acetyl-leucine may be initiated when a subject is asymptomatic to delay the onset of LSD or one or more symptoms of LSD that would otherwise be expected to develop according to typical disease progression. In another embodiment, the subject is symptomatic. Administration of acetyl-leucine may be initiated when a subject has some symptoms to delay the onset of one or more additional symptoms of LSD that would otherwise be expected to develop according to typical disease progression. Subjects in need thereof may continue to receive treatment with acetyl-leucine for periods described herein. In one embodiment, treatment prevents the onset of one or more symptoms of LSD that would otherwise be expected to develop according to typical disease progression.

[0058] In one embodiment, "treating an LSD or one or more symptoms of an LSD" means reducing the severity of an LSD or reducing or eliminating the severity of one or more pre-existing symptoms associated with an LSD. The severity of an LSD or the severity of a pre-existing symptom may be assessed using a known scale, index, rating, or score, such as those described herein by way of example, or another suitable test for assessing severity. For example, the scale, index, rating, score, or other suitable test may correspond to the overall severity of an LSD or the severity of one or more symptoms associated with an LSD. In one embodiment, treatment improves the assessment, such as from a value or degree characteristic of a symptomatic patient to a value or degree characteristic of an asymptomatic patient.

[0059] In one embodiment, "treating an LSD or one or more symptoms of an LSD" means delaying the progression of an LSD or one or more symptoms associated with an LSD over time, or reversing the progression of an LSD or one or more symptoms associated with an LSD over time, relative to typical disease progression. The time period over which the treatment delays or reverses progression may correspond to the duration of the treatment as described herein. The treatment may delay or reverse progression for, for example, about 7 days or more, about 2 weeks or more, about 3 weeks or more, about 1 month or more, about 6 weeks or more, about 7 weeks or more, or about 2 months or more. For example, the treatment delays or reverses progression for about 3 months or more, about 4 months or more, about 5 months or more, or about 6 months or more. Further, for example, it slows or reverses progression over a period of about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment may slow or reverse the progression of LSD or one or more symptoms associated with LSD over the patient's lifetime.

[0060] In one embodiment, "treating an LSD or one or more symptoms of an LSD" refers to slowing the progression of an LSD or one or more symptoms of an LSD over time compared to typical disease progression. As used herein, "slowing the progression of an LSD or one or more symptoms associated with an LSD over time" or the like refers to slowing and / or stopping the progression of an LSD or one or more symptoms of an LSD (e.g., slowing and / or stopping the worsening or increasing severity of an LSD or one or more symptoms of an LSD). Disease progression may be determined using a known scale, index, rating, or score, such as those described herein by way of example, or other suitable test for assessing progression. For example, the scale, index, rating, score, or other suitable test may correspond to overall LSD progression or the progression of one or more symptoms associated with an LSD. In one embodiment, "delaying the progression of an LSD or one or more symptoms associated with an LSD" means that a subject's disease severity value (e.g., overall severity or the severity of one or more symptoms) as determined by a known scale, index, rating, etc., or another suitable test for assessing severity does not significantly increase (e.g., remains at least substantially constant). In one embodiment, "delaying the progression of an LSD or the progression of one or more symptoms of an LSD" means increasing the time it takes a subject to reach a severity value (e.g., decreasing the rate of change that increases severity) or preventing a subject from reaching that value according to a known scale, index, rating, score, etc., or another suitable test for assessing progression compared to a value corresponding to typical disease progression. For example, progression can be said to be delayed when the time to reach a severity value takes at least 5% longer than the time observed for typical disease progression. Further, for example, an increase of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of the time is observed.The time period over which a treatment slows the progression of an LSD or one or more symptoms of an LSD may correspond to the duration of the treatment as described herein. In one embodiment, the treatment slows progression for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In another embodiment, the treatment slows progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. The treatment may slow progression over the patient's lifetime.

[0061] In one embodiment, "treating an LSD or one or more symptoms of an LSD" means reversing the progression of an LSD or one or more symptoms of an LSD over time. As used herein, "reversing the progression of an LSD or the progression of one or more symptoms of an LSD over time" or the like means reducing the severity of an LSD or the severity of one or more symptoms of an LSD or halting the progression of an LSD or one or more symptoms of an LSD. Disease progression and severity may be determined using a known scale, index, rating, or score, such as those described herein by way of example, or another suitable test for assessing progression and severity. For example, the scale, index, rating, or score, or other suitable test, may correspond to the progression and severity of an LSD overall, or to the progression and severity of one or more symptoms associated with an LSD. In one embodiment, "reversing the progression of an LSD or one or more symptoms of an LSD over time" means that a disease severity value (e.g., overall severity or the severity of one or more symptoms) as determined by a known scale, index, rating, score, etc., or another suitable test for assessing severity, improves over time (i.e., shows a decrease in severity over time). The time period over which a treatment reverses the progression of an LSD or one or more symptoms of an LSD may correspond to the duration of a treatment as described herein. In one embodiment, a treatment reverses progression for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In another embodiment, a treatment reverses progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. A treatment may reverse progression over the patient's lifetime.

[0062] In one embodiment, "treating an LSD or one or more symptoms of an LSD" means improving a biochemical marker of an LSD in a subject (e.g., increased levels of secondary biochemical changes or accumulated metabolites resulting from primary accumulation). Biochemical markers signal disease activity and may provide an ongoing indicator of disease severity and progression over time. In one embodiment, the biochemical marker is improved relative to a control value. In one embodiment, the biochemical marker is selected from increased lysosomal mass and increased glycosphingolipid (GSL) levels. In one embodiment, the biochemical marker is increased lysosomal mass, and the treatment reduces the lysosomal mass in the subject. In one embodiment, the biochemical marker is increased glycosphingolipid (GSL) levels, and the treatment reduces GSL levels in the subject. In one embodiment, the treatment improves the biochemical marker over time. For example, in one embodiment, improving a biochemical marker over time means that the treatment improves the biochemical marker over time toward a control value, prevents the progression of the biochemical marker over time, and / or slows the progression of the biochemical marker over time, relative to typical disease progression. The time over which the treatment improves the biochemical marker may correspond to the duration of the treatment as described herein. In one embodiment, the treatment improves the biochemical marker for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In further embodiments, the treatment improves the biochemical marker for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. The treatment may improve the biochemical marker over the patient's lifetime.

[0063] "Symptoms" of LSD include any clinical or laboratory symptoms associated with LSD, and are not limited to those that can be felt or observed by a subject. Symptoms as described herein include, but are not limited to, neurological and psychiatric symptoms. Examples of neurological symptoms include ataxia, hypokinesia, rigidity, tremor, or other movement disorders such as dystonia, central oculomotor disorders such as vertical and horizontal supranuclear saccadic / gaze palsy, and neuropsychological disorders such as dementia. Examples of psychiatric symptoms include depression, behavioral disorders, or psychosis. The onset of symptoms may range from birth to adulthood.

[0064] For example, the progression of an LSD or one or more symptoms of an LSD can be monitored over time or with treatment by using one or more known tests at two or more time points and comparing the results. For example, the Scale for the Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), the International Cooperative Ataxia Rating Scale (ICARS), the brief ataxia rating scale (BARS), the modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L (EQ-5D-5L), the visual analogue scale (VAS), the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wechsler Intelligence Scale for Children-IV (WEIS-IV ... Disease progression and / or severity can be assessed using the World Assessment for Children-IV (WISC-IV), the Montreal Cognitive Assessment (MoCA), or other appropriate tests. For certain LSDs, such as NPC, specific scores, such as the clinical severity score (CSS) and the annual severity increment score (ASIS), have been developed and validated over the past few decades. For example, the severity of an NPC patient can be quantified by assigning a CSS, which assesses various disease parameters (gait, seizures, eye movements, etc.) and assigns a score out of 5 to each parameter.The higher the score, the greater the severity. The ASIS quantifies the annual rate of change in CSS, calculated by dividing CSS by the patient's age. In this regard, certain scores on these tests are characteristic of symptomatic LSD patients and attest to the progression and / or severity of the disease.

[0065] Thus, for example, "treating an LSD or one or more symptoms of an LSD" may be equivalent to achieving an improved assessment, such as a SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA score, or other test result suitable for characterizing an LSD subject. For example, in one embodiment, "reducing the severity of an LSD, or reducing or eliminating the severity of one or more existing symptoms of an LSD" means improving a SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA score, or another suitable test result assessing severity, such as improving a score or result from a severity value characteristic of a symptomatic subject to a value characteristic of an asymptomatic subject. In another embodiment, "delaying the progression of an LSD or one or more symptoms of an LSD" means that a subject's SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA score, or another suitable test for assessing progression, does not significantly increase (e.g., remains at least substantially constant). In a further embodiment, "delaying the progression of an LSD or one or more symptoms of an LSD" means preventing or increasing the time it takes for a subject's SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA score, or another suitable test for assessing progression, to reach a value compared to that of typical disease progression.In another embodiment, "reversing the progression of an LSD or the progression of one or more symptoms of an LSD over time" means that a subject's SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA scores, or results from another appropriate test for assessing progression, improve over time (i.e., show a decrease in severity over time).

[0066] For example, to assess overall neurological status, the mDRS, a four-domain scale (ambulation, manipulation, language, and swallowing), may be administered. Cerebellar function may be assessed using the SARA, an eight-item clinical rating scale (gait, stance, sitting, language, fine motor function, and taxis; ranging from 0 to 40, with 0 being the best neurological condition and 40 being the worst), and the SCAFI, which includes the 8-m walking time (8MW; performed by having the patient walk twice as fast from one line to another, excluding turns), the 9-Hole Peg Test (9HPT), and the number of "PATA" repetitions over 10 seconds. Subjective disability and quality of life may be assessed using the EQ-5D-5L questionnaire and VAS. To assess oculomotor function, 3D videooculography (EyeSeeCam) may be used to measure peak saccade velocity, acquisition of smooth pursuit, peak slow-phase velocity of gaze-evoked nystagmus (gaze maintenance function), peak slow-phase velocity of optokinetic nystagmus, and acquisition of the horizontal vestibulo-ocular reflex. To assess cognitive status, the WAIS-R or WISC-IV, and MoCA, which assess different cognitive domains including attention and concentration, executive function, memory, language, visuo-constructive skills, conceptual thinking, calculation, and orientation, with a maximum score of 30 and a cutoff score of 26, may be used. Those skilled in the art will know how to administer these and other such tests.

[0067] Acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be administered in a dose ranging from about 500 mg to about 15 g per day, or from about 500 mg to about 10 g per day, for example, in the range of about 1.5 g to about 10 g per day, optionally by solid oral or liquid oral route. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be administered in a dosage according to the dosage prescribed for adults for Tanganil®, for example, in a dose of 1.5 g to 2 g per day, 3-4 tablets taken twice a day, in the morning and in the evening.

[0068] If one enantiomer is administered, the dosage may be reduced accordingly. For example, if only acetyl-L-leucine or only acetyl-D-leucine is administered, the dosage may be in the range of about 250 mg to about 15 g per day, about 250 mg to about 10 g per day, or about 250 mg to about 5 g per day, e.g., about 0.75 g to about 5 g per day.

[0069] In one embodiment, the dosage ranges from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, or from about 1.5 g to about 7 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 g to about 15 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8, or 9 g to about 10 g per day. It may be more than about 1.5 g per day but less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 g per day. In one embodiment, the dosage ranges from about 4 g to about 6 g per day. In another embodiment, the dosage ranges from about 4 g to about 5 g per day. In one embodiment, the dosage is about 4.5 g per day. In one embodiment, the dosage is about 5 g per day. In one embodiment, these doses are administered in a solid oral dosage form, particularly a tablet. In another embodiment, these dosages are for acetyl-leucine when it is in its racemic form. When enantiomeric excess is present, the dosage for acetyl-leucine may be lower than those listed here, for example, about 50% lower. Thus, the above-mentioned dosage ranges when halved are also expressly encompassed by the present disclosure.

[0070] The total daily dose can be distributed over multiple doses, i.e., administration can be performed more than once a day to achieve the total daily dose. For example, the number of tablets required to provide the total daily dose of acetyl-leucine can be divided into two doses (e.g., morning and evening) or three doses (e.g., morning, midday, and evening). Each dose can be appropriately administered with or without food. For example, acetyl-leucine can be administered about 1 or about 2 hours before a meal, such as at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about 1 hour before a meal, or about 1 hour, about 2 hours, or about 3 hours after a meal, such as at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours after a meal. For example, a total daily dose of 4.5 g of acetyl-DL-leucine might be administered as three Tanganil® (or equivalent) tablets before, during, or after breakfast, three more tablets before, during, or after lunch, and three more tablets before, during, or after dinner.

[0071] Administration of acetyl-leucine according to the present disclosure may be initiated before or after a subject is found to have a genetic, biochemical, or other similar identifiable marker for LSD; in the former case, when the subject is suspected of having or at risk of having LSD. Administration may be initiated at or around the time the subject is found to have a genetic, biochemical, or other similar identifiable marker for LSD. Similarly, administration may be initiated before, around, or after the subject is diagnosed with LSD, such as before, at, around, or after the subject is found to have a genetic, biochemical, or other similar identifiable marker. Administration of acetyl-leucine may be initiated when the subject is symptomatic or asymptomatic. In particular, one advantage of treatment with acetyl-leucine according to the present disclosure is that administration of acetyl-leucine may be initiated before a subject exhibits symptoms of LSD (other than genetic and / or biochemical markers, i.e., the subject is asymptomatic) or before a subject exhibits one or more symptoms considered hallmarks of the disease, but early after the subject is identified as having genetic and / or biochemical markers. As described herein, treatment may delay the onset of LSD or one or more symptoms associated with LSD. Treatment may also be continued for a period of time as described herein.

[0072] As described herein, an advantage of treatment with acetyl-leucine according to the present disclosure is that acetyl-leucine may be administered over an extended period of time, for example, to slow or even reverse the progression of LSD or one or more symptoms of LSD in a subject compared to typical disease progression. The treatment period may be, for example, about 7 days or more, about 2 weeks or more, about 3 weeks or more, about 1 month or more, about 6 weeks or more, about 7 weeks or more, or about 2 months or more. In one embodiment, it is about 3 months or more, about 4 months or more, about 5 months or more, or about 6 months or more. The treatment period may be about 1 year or more, about 2 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment period may be the patient's lifespan.

[0073] Any and all combinations of dosage forms, dosage amounts, administration schedules, and treatment durations are contemplated and encompassed by the present invention. In one embodiment, the dosage is about 4 g to about 10 g per day taken in one, two, or three administrations per day for a treatment duration of about 2 months or more. In another embodiment, the dosage is greater than 4 g and not more than 5 g per day taken in one, two, or three administrations per day for a treatment duration of about 6 months or more. The dosage form may be a solid oral dosage form, particularly a tablet.

[0074] The pharmaceutical compositions may be used as monotherapy (e.g., use of the active agent alone) to treat an LSD in a subject. Alternatively, the pharmaceutical compositions can be used as an adjunct to or in combination with other known therapies, e.g., to treat an LSD in a subject.

[0075] All LSDs, which can be classified in various ways, are within the scope of this disclosure. In one embodiment, the LSD is selected from any of glycogen storage diseases, mucopolysaccaridoses, mucolipidoses, oligosaccharidoses, lipidoses, sphingolipidoses, and lysosomal transport diseases.

[0076] The sphingolipidoses may be selected from any of Niemann-Pick disease types A / B, Gaucher disease types I, II, and III, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, Morquio B disease, GM2 gangliosidoses, metachromatic leukodystrophy, Farber disease, multiple sulfatase deficiency, lysosomal acid lipase deficiency, and galactosialidosis. In one embodiment, the sphingolipidosis is selected from Niemann-Pick disease type A, GM1 gangliosidosis, Tay-Sachs disease, the AB variant of Tay-Sachs disease, and Sandhoff disease.

[0077] The mucolipidosis may be selected from any of mucolipidosis I, mucolipidosis II, mucolipidosis III, and mucolipidosis IV. In one embodiment, the mucolipidosis is mucolipidosis II or mucolipidosis III.

[0078] The mucopolysaccharidosis can be selected from any of MPS IH, MPS IHS, MPS IS, MPS IIA, MPS IIB, MPS IIIA-D, MPS IVA, MPS VI, MPS VII, and MPS IX. In one embodiment, the mucopolysaccharidosis is MPS III or MPS VII. In one embodiment, the mucopolysaccharidosis is MPS IIIB.

[0079] The oligosaccharidosis may be selected from any of beta-mannosidosis, alpha-fucosidosis, and aspartylglucosaminuria, hi one embodiment, the oligosaccharidosis is aspartylglucosaminuria.

[0080] The lipidosis may be selected from Niemann-Pick disease type C, Niemann-Pick disease type D, neuronal ceroid lipofuscinosis (including types I through X), and Wolman disease. In one embodiment, the lipidosis is Niemann-Pick disease type C.

[0081] The glycogen storage disease may be selected from infantile-onset Pompe disease, late-onset Pompe disease, and Danon disease.

[0082] The lysosomal trafficking disorder may be selected from cystinosis, pycnodysostosis, sialic acid storage disease, and infantile free sialic acid storage disease.

[0083] An LSD may be a primary lysosomal hydrolase defect, a post-translational processing defect of lysosomal enzymes, a trafficking defect for lysosomal enzymes, a defect in lysosomal enzyme protection, a defect in soluble non-enzymatic lysosomal proteins, a transmembrane (non-enzyme) protein defect, or an unclassified defect.

[0084] In one embodiment, the LSD is selected from a primary lysosomal hydrolase defect. Primary lysosomal hydrolase deficiencies include, but are not limited to, Tay-Sachs disease (β-hexosaminidase A defect), Sandhoff disease (β-hexosaminidase A+B defect), Fabry disease (α-galactosidase A defect), Krabbe disease (β-galactosyl ceramidase defect), Niemann-Pick disease types A and B (sphingomyelinase defect), metachromatic leukodystrophy (arylsulphatase A defect), MPS IH (Hurler syndrome; α-iduronidase defect), MPS IS (Scheie syndrome), and Fabry disease (α-galactosidase A defect). syndrome; α-iduronidase deficiency), MPS IH-S (Hurler-Scheie syndrome; α-iduronidase deficiency), MPS II (Hunter syndrome; iduronate sulfatase deficiency), MPS IIIA (Sanfilippo A syndrome; heparan sulfamidase deficiency), MPS IIIB (Sanfilippo B syndrome; acetyl α-glucosaminidase deficiency), MPS IIIC (Sanfilippo C syndrome);Acetyl-coenzyme A (acetyl CoA):α-glucosaminide N-acetyltransferase defect), MPS IIID (Sanfilippo D syndrome; N-acetylglucosamine-6-sulphatase defect), MPS IV A (Morquio A disease; acetylgalactosamine-6-sulphatase defect), MPS IVB (Morquio B disease; β-galactosidase defect), MPS V (redesignated MPS IS), MPS VI (Maroteaux-Lamy syndrome) Syndrome; acetylgalactosamine-4-sulphatase (arylsulphatase B) defect), MPS VII (Sly Syndrome; β-glucuronidase defect), MPS IX (hyaluronidase defect), Wolman / cholesteryl ester storage disease (WD; acid lipase defect), Pompe disease (Type II;α 1,4-glucosidase deficiency, aspartylglucosaminuria (glycosylasparaginase deficiency), fucosidosis (α-fucosidase deficiency), α-mannosidosis (α-mannosidase deficiency), β-mannosidosis (β-mannosidase deficiency), Schindler disease (N-acetylgalactosaminidase deficiency), sialidosis / ML I (α-neuraminidase deficiency) defect), infantile neuronal ceroid lipofuscinosis (CLN1; (palmitoyl protein thioesterase defect), late infantile neuronal ceroid lipofuscinosis (CLN2;Carboxypeptidase defect), early infantile GM1 gangliosidosis, late infantile GM1 gangliosidosis, adult infantile GM1 gangliosidosis, Gaucher Disease Type 1 (Non-Neuronopathic), Gaucher Disease Type 2 / 3 (Neuronopathic), Neuronal Ceroid Lipofuscinosis Type 4 (CLN4; Kufs disease), Adult NCL, palmitoyl-protein thioesterase-1 deficiency (Type A) Cathepsin F deficiency (Type B), Neuronal Ceroid Lipofuscinosis Type 10 (CLN10; Congenital Cathepsin D Deficiency), Pycnodysostosis (Cathepsin K defect), Infantile-Onset Pompe Disease, Late-Onset Pompe Disease, Farber Disease (Farber's lipogranulomatosis; ceramidase deficiency; Fibrocytic dysmucopolysaccharidosis);Lipogranulomatosis) and Galactosialidosis (protective protein cathepsin A defect, PPCA defect). In one embodiment, the primary lysosomal hydrolase deficiency is selected from Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease type A, Niemann-Pick disease type B, neuronal ceroid lipofuscinosis, Gaucher disease, Fabry disease, Krabbe disease, GM1 gangliosidosis, GM2 gangliosidosis, metachromatic leukodystrophy, and Farber disease. In one embodiment, the primary lysosomal hydrolase deficiency is selected from Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease type A, Niemann-Pick disease type B, and GM1 gangliosidosis.

[0085] In one embodiment, the LSD is selected from post-translational processing defects of lysosomal enzymes, including, but not limited to, mucosulphatidosis (MSD; multiple sulfatase defect), MLII (I-cell disease; N-acetyl glucosamine phosphoryl transferase defect), and MLIII (pseudo-Hurler polydystrophy; N-acetyl glucosamine phosphoryl transferase defect).

[0086] In one embodiment, the LSD is selected from lysosomal enzyme trafficking defects, including, but not limited to, mucolipidosis type II (I-cell disease; N-acetyl glucosamine phosphoryl transferase defect), mucolipidosis type IDA (pseudo-Hurler polydystrophy; N-acetyl glucosamine phosphoryl transferase defect), and mucolipidosis type IIIC.

[0087] In one embodiment, the LSD is a deficiency in lysosomal enzyme protection, including, but not limited to, galactosialidosis (protective protein cathepsin A (PPCA) deficiency).

[0088] In one embodiment, the LSD is a soluble non-enzymatic lysosomal protein deficiency, including, but not limited to, GM2 activator protein deficiency (variant AB), Niemann-Pick disease type C2 (NPC2), and sphingolipid activator protein (SAP) deficiency.

[0089] In one embodiment, the LSD is a transmembrane (non-enzyme) protein deficiency. Transmembrane (non-enzyme) protein deficiencies include, but are not limited to, Danon disease (lysosomal-associated membrane protein 2 (LAMP2) deficiency), NPC (NPC1 deficiency), cystinosis (cystinosin deficiency), infantile free sialic acid storage disease (ISSD; sialin defect), Sarlat's disease (free sialic acid storage disease; sialin deficiency), juvenile neuronal ceroid lipofuscinosis (CLN3, Batten disease), adult neuronal ceroid lipofuscinosis (Kufs disease; Adult NCL), pamoyl-protein thioesterase-1 deficiency (Type A), and cathepsin F deficiency (Type B). deficiency (Type B), neuronal ceroid lipofuscinoses (NCL) (CLN6, CLN7, and CLN8), and mucolipidosis type IV (mucolipin defect). In one embodiment, the LSD is Niemann-Pick disease type C1 or Niemann-Pick disease type C2.

[0090] In one embodiment, the LSD is an unclassified deficiency disorder. Unclassified deficiencies include, but are not limited to, neuronal ceroid lipofuscinosis (NCL) (CLN5 and CLN9).

[0091] The LSDs treated by the compositions and methods of the present invention may be any of neuronal ceroid lipofuscinosis, primary glycosphingolipidosis (i.e., Gaucher, Fabry, GM1, GM2 gangliosidoses, Krabbe, and metachromatic leukodystrophy (MLD)), Farber disease, and multiple sulfatase deficiency. In one embodiment, the LSD has significant central nervous system (CNS) involvement. For example, the LSD may be selected from NPC, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, or Fabry disease.

[0092] In one embodiment, the LSD is Niemann-Pick disease type A. In another embodiment, the LSD is Niemann-Pick disease type B. In another embodiment, the LSD is Niemann-Pick disease type C (C1 or C2). Pick disease is a heterogeneous group of autosomal recessive LSDs. Shared cellular features include hepato-splenomegaly as well as abnormal sphingomyelin (SM) accumulation in mononuclear phagocytes and parenchymal tissues. Of the three major subgroups (AC), NPC (formerly classified as NPC and NPD, now recognized as a single disease) is classified as a fatal neurovisceral LSD caused by abnormal intracellular cholesterol transport-induced accumulation of unesterified cholesterol in late endosomal / lysosomal compartments. Outside the CNS, cellular characteristics of NPC include abnormal accumulation of unesterified cholesterol and other lipids (e.g., GSLs) in late endosomal / lysosomal compartments. Conversely, there is no net elevation of cholesterol in the CNS (although there is altered distribution), but there are highly elevated levels of GSLs. Progressive neurodegeneration is particularly characterized by the sequential degeneration of GABAergic Purkinje neurons in the cerebellum, which parallels the onset and progression of cerebellar ataxia and other aspects of neuronal dysfunction seen during the course of NPC. Genetic studies have shown that NPC disease is caused by mutations in either the Npc1 or Npc2 gene. The precise mechanistic relationship between these two genes remains unknown, and the functional role of these proteins remains enigmatic. NPC1 encodes a multi-transmembrane protein of the limiting membrane of late endosomes / lysosomes, whereas NPC2 is a soluble cholesterol-binding protein of lysosomes. When NPC1 is inactivated, sphingosine is the first lipid to accumulate, suggesting that NPC1 plays a role in the transport of sphingosine from lysosomes, where it is normally produced as part of sphingolipid catabolism.Elevated sphingosine, in turn, causes a defect in calcium entry into acidic stores, resulting in greatly reduced calcium release from this compartment. This subsequently prevents late endosome-lysosome fusion, a calcium-dependent process, and leads to the secondary accumulation of lipid cargo (cholesterol, sphingomyelin, and glycosphingolipids) that passes through the late endocytic pathway. Other secondary consequences of inhibiting NPC1 function include defective endocytosis and an inability to remove autophagic vacuoles. The NPC1 / NPC2 cellular pathway has been shown to be targeted by pathogenic mycobacteria to promote their survival in late endosomes.

[0093] Tay-Sachs disease is a fatal genetic disorder of lipid metabolism characterized by a deficiency of the A isoenzyme of β-hexosaminidase, particularly in CNS tissues. Mutations in the HEXA gene, which encodes the α subunit of β-hexosaminidase, cause A isoenzyme deficiency. Tay-Sachs disease is the prototype of a group of disorders, such as GM2 gangliosidosis, characterized by defective GM2 ganglioside degradation. GM2 ganglioside (monosialylated ganglioside 2) accumulates in neurons beginning during fetal development.

[0094] Sandhoff disease results from a deficiency of both the A and B (basic) isozymes of β-hexosaminidase. Mutations in the HEXB gene, which encodes the β subunit of β-hexosaminidase, cause B isozyme deficiency.

[0095] GM1 gangliosidosis is caused by a deficiency of β-galactosidase, which results in the lysosomal accumulation of GM1 ganglioside (monosialylated ganglioside 1).

[0096] Fabry disease is caused by a deficiency of α-galactosidase, which results in the intralysosomal accumulation of ceramide trihexoside.

[0097] In one embodiment, the LSD is selected from Tay-Sachs disease, AB variant of Tay-Sachs disease, Sandhoff disease, Niemann-Pick type A, mucolipidosis II, mucolipidosis III, MPS III, MPS VII, GM1 gangliosidosis, and aspartylglucosaminuria. In one embodiment, the LSD is Sandhoff disease. In one embodiment, the LSD is Tay-Sachs disease. In one embodiment, the LSD is AB variant of Tay-Sachs disease. In one embodiment, the LSD is mucolipidosis type II. In one embodiment, the LSD is mucolipidosis type III. In one embodiment, the LSD is GM1 gangliosidosis. In one embodiment, the LSD is MPS III. In one embodiment, the LSD is MPS VII. In one embodiment, the LSD is Niemann-Pick type A. In one embodiment, the LSD is aspartylglucosaminuria.

[0098] In one embodiment, the LSD is not Niemann-Pick disease. In one embodiment, the LSD is not Niemann-Pick disease type C.

[0099] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats weight loss, gait deterioration, and / or motor decline associated with Niemann-Pick disease (e.g., Niemann-Pick Type C or Type A) or mucolipidosis Type II. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may slow, reverse, eliminate, reduce the severity of, or delay the onset of weight loss, gait deterioration, and / or motor decline associated with Niemann-Pick disease (e.g., Niemann-Pick Type C or Type A) or mucolipidosis Type II. In one embodiment, the weight loss, gait deterioration, and / or motor decline are associated with Niemann-Pick Type A or mucolipidosis Type II.

[0100] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats gait deterioration, motor dysfunction, and / or reduced mobility associated with Sandhoff disease. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may slow or reverse the progression, eliminate or reduce the severity, or delay the onset of gait deterioration, motor dysfunction, and / or reduced mobility associated with Sandhoff disease.

[0101] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats the poor coordination, tremors, reduced mobility, cognitive impairment, and / or gait deterioration associated with Tay-Sachs disease. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may slow or reverse the progression, reduce or eliminate the severity, or delay the onset of the poor coordination, tremors, reduced mobility, cognitive impairment, and / or gait deterioration associated with Tay-Sachs disease.

[0102] Also provided is a method of treating LSD or one or more symptoms of LSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof.

[0103] A "therapeutically effective amount" of a drug is the amount of drug required to produce a desired effect, which, for the purposes of this disclosure, may be therapeutic and / or prophylactic, when administered to a subject. The dosage may be determined according to various parameters, such as the specific form of acetyl-leucine used; the age, weight, and condition of the patient being treated; the type of illness; the route of administration; and the required regimen. A physician will be able to determine the required route of administration and dosage for any particular patient. For example, the daily dosage may be about 10 to about 225 mg / kg body weight, about 10 to about 150 mg / kg body weight, or about 10 to about 100 mg / kg body weight.

[0104] Also disclosed is a kit for treating an LSD in a subject in need thereof (e.g., a subject having, suspected of having, or at risk of having an LSD), which comprises a means for diagnosing or prognosing an LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof.

[0105] The means for diagnosing or predicting LSDs may include specific binding agents, probes, primers, primer pairs or combinations thereof, enzymes, including antibody fragments, or antibodies, which are capable of detecting or aiding in the detection of LSDs, as defined herein. The kit may also include LysoTracker®, a fluorescent marker, commercially available from both Invitrogen and Lonza. LysoTracker® may be blue, pale blue, yellow, green, or red.

[0106] The kit also includes acetyl-leucine or a pharmaceutically acceptable salt thereof, as defined herein. The kit may further include a buffer or aqueous solution. The kit may further include instructions for using the acetyl-leucine or a pharmaceutically acceptable salt thereof in the methods of the invention.

[0107] In a further embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of providing neuroprotection in a subject having, suspected of having, or at risk of having LSD.

[0108] As used herein, "neuroprotection" and its cognates refer to preventing, slowing, and / or reversing the progression of neurodegeneration, including, but not limited to, the progressive loss of neuronal structure, the progressive loss of neuronal function, and / or the progressive death of neurons. Providing neuroprotection may result in delaying the onset of an LSD or one or more symptoms of an LSD that would otherwise be expected to manifest according to a typical disease progression, reducing the severity of an LSD or reducing the severity of or eliminating one or more pre-existing symptoms associated with an LSD, delaying the progression of an LSD or one or more symptoms of an LSD over time compared to a typical disease progression, and / or reversing the progression of an LSD or one or more symptoms of an LSD over time. The period over which neuroprotection is provided may coincide with the period of treatment, as described herein. The treatment may provide neuroprotection for, for example, about 7 days or more, about 2 weeks or more, about 3 weeks or more, about 1 month or more, about 6 weeks or more, about 7 weeks or more, or about 2 months or more. Further examples include the treatment providing neuroprotection for about 3 months or more, about 4 months or more, about 5 months or more, or about 6 months or more. In another example, it provides neuroprotection for about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment may provide neuroprotection for the patient's lifetime.

[0109] As evidenced by experimental examples, the inventors believe that acetyl-leucine acts as a neuroprotective agent and inhibits neurodegeneration that might otherwise be expected to occur.

[0110] In one embodiment, there is a method for providing neuroprotection in a subject having, suspected of having, or at risk of having LSD, comprising administering to the subject a therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof.

[0111] Also disclosed is a kit comprising a means for diagnosing or prognosing an LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof, for providing neuroprotection in a subject having, suspected of having, or at risk of having an LSD.

[0112] The present disclosure further includes the use of acetyl-leucine or a pharmaceutically acceptable salt thereof as a neuroprotective agent in a subject having, suspected of having, or at risk of having LSD.

[0113] Every feature described herein (including any accompanying claims, abstract and drawings), and / or every step of any method so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some such features and / or steps are mutually exclusive.

[0114] Experimental Example The present invention is described in further detail in the following experimental examples, which demonstrate the utility of acetyl-leucine in treating LSD in a subject and providing neuroprotection in said subject.

[0115] Experimental Example 1 In vivo mouse studies - methods Mouse model This study demonstrates the development of an authentic mouse model of NPC, Npc1 - / - (BALB / cNctr-Npc1 m1N / J) mice were utilized, which are null for the NPC1 protein and display all the features of clinical disease (Loftus, 1997).

[0116] This mutant strain arises spontaneously, has a lifespan ranging from 10 to 14 weeks, and therefore has a more acute disease course than the majority of patients. These mutant mice have been successfully used not only to determine the ontogeny of the disease and its underlying pathogenic mechanisms, but also to evaluate experimental treatments. Analyses using these mice have been performed at the whole animal, cellular, and molecular levels (Baudry, 2003; Smith, 2009; Cologna, 2014; Cologna, 2012). It is the most intensively studied animal model of NPC.

[0117] Before about 4–5 weeks of age, Npc1 - / - Mice have no discernible behavioral signs of illness that distinguish them from wild-type littermates. The first signs of behavioral defects, such as tremors and ataxic gait, appear by 5-6 weeks, impaired motor coordination becomes more evident by 7-8 weeks, and by 9-10 weeks ataxia progresses, accompanied by increasing loss in body weight and poor coat condition as feeding and water intake become more difficult (humane end points apply) (Smith, 2009).

[0118] Wild type (Npc1 + / + ) Littermates were used as controls.

[0119] Treatment Protocol A group of Npc1 - / - Mice and a group of Npc1 + / + Mice were treated from weaning (3 weeks of age) with 0.1 g / kg acetyl-DL-leucine provided in mouse chow. As a control, the segregant Npc1 - / - and Npc1 + / + Mice were left untreated (treated).

[0120] Coat Condition Npc1 with and without acetyl-DL-leucine treatment- / - The coat condition of the mice was compared by simple observation of 9-week-old mice.

[0121] Weight Data Animals were weighed twice weekly, and weights were averaged (mean) across all mice in each group and compared.

[0122] Gait analysis Gait analysis was performed on mice at 8 weeks of age using the CatWalk® 15.0 system according to the manufacturer's instructions (Noldus, Nottingham, UK). Five trials were recorded per animal.

[0123] The CatWalk® parameters measured were: 1. Stand Mean: The average duration (s) of the paw in contact with the glass plate; 2. Step cycle: duration (s) between two successive contacts of the same paw; 3. Duty cycle: the percentage of time the paws are in contact with the plate compared to the time to complete a step cycle; 4. Step sequence (AB): The percentage of time spent walking in an alternating LF-RH-RF-LH pattern (LF: left anterior; RH: right posterior; RF: right anterior; LH: left posterior); 5. Cadence: steps per second in the trial; 6. Diagonal Support: The percentage of time that the diagonal paws are in contact with the glass plate simultaneously (RF&LH or RH&LF).

[0124] Motor function analysis Motor function analysis was performed on 8- and 9-week-old mice using an Open Field Activity Monitor according to the manufacturer's instructions (Linton Instruments, Amlogger Software). Each mouse was placed in a plastic cage with bedding and analyzed for 5 minutes. Rears were counted manually.

[0125] The motor function parameters measured were as follows: 1. Center Rearing: Rearing the mouse on its hind legs without support; 2. Rearing: Rearing of the mouse on its hind legs with and without cage wall support; 3. Activity: The regular movement of an animal, including walks; 4. Front to Back (FR) count: movement of the animal from the front to the back of the cage; 5. Active Time: Duration of activity regardless of movement (s / min); 6. Mobile Time: Mobility duration (seconds / minutes); 7. Rearing Time: The duration of any rearing.

[0126] result Court Condition Figure 1B shows untreated (treated) Npc1 - / - Age-matched littermates are shown. - / - Mice were observed to have poor coat condition at 9 weeks of age, as they had difficulty eating and drinking (see Figure 1B).

[0127] In sharp contrast, Figure 1A shows that Npc1 mice treated with acetyl-DL-leucine from weaning - / - Shown is a mouse Npc1 treated with acetyl-DL-leucine. - / - Mice were wild-type (Npc1 + / + ) had a smooth and glossy coat, reminiscent of its littermates (see Figure 1A).

[0128] Weight data As can be seen in Figure 2A, the wild type (Npc1 + / + ) Mice steadily gained weight over the course of the study (i.e., from 3 to 10 weeks of age). Furthermore, Figure 2A shows that at each time point (Npc1 - / - Untreated (naive), n = 1; Npc1 - / - Acetyl-DL-leucine 0.1g / kg, n=3; Npc1 + / + Untreated (naive), n = 3; Npc1 + / + 0.1 g / kg of acetyl-DL-leucine, n=2), and the mean body weight per group of mice is shown.

[0129] Treatment with acetyl-DL-leucine did not significantly affect this weight gain.

[0130] Npc1 - / - Mice were initially Npc1 + / + Body weight gain was similar to that of the control group. - / - The mice began losing weight at six weeks of age, and by the end of the experiment (at 10 weeks of age), they were weighing as little as they had at just four weeks of age.

[0131] Treatment with acetyl-DL-leucine delayed these weight loss symptoms by two weeks compared to the untreated group.

[0132] Npc1 with and without acetyl-DL-leucine treatment - / -The comparison of the weight changes of the mice is shown in Figure 2B. In particular, Figure 2B shows that Npc1 - / - For mice only, the % change in body weight per group of mice at each time point is shown. The beneficial effect of acetyl-DL-leucine treatment in slowing weight loss is evident from this figure.

[0133] Gait analysis The results of gait analysis are shown in Figure 3. Diagonal support, cadence, and step sequence data are shown in Figures 3A-3C, respectively. Figures 3D and 3E show front paw (FP) data (stand mean and step cycle in Figure 3D; duty cycle in Figure 3E). Figures 3F and 3G show hind paw (HP) data (stand mean and step cycle in Figure 3F; duty cycle in Figure 3G). Data are expressed as mean ± SEM. + / + n=3 for Npc1 + / + n=2 per treated, Npc1 - / - n=1 for untreated (thus no statistical analysis was performed), Npc1 - / - n=3 per treated.

[0134] The first bar in each graph represents the wild type (Npc1 + / + ) Gait characteristics of mice.

[0135] The second bar in each graph represents wild-type (Npc1) treated with acetyl-DL-leucine. + / + ) shows the gait characteristics of mice. There were no significant differences in gait characteristics between these mice and their naive (untreated) littermates.

[0136] The third bar in each graph is Npc1 - / - Figure 1 shows the walking characteristics of Npc1 mice. + / + The mice exhibited impaired gait compared with control mice: they spent significantly less time, if at all, in diagonal support (Fig. 3A) or step sequence (Fig. 3C), and their hind paw function in stand mean (Fig. 3F) and duty cycle (Fig. 3G) were also dramatically impaired.

[0137] The fourth bar in each graph represents Npc1 treated with acetyl-DL-leucine. - / - Figure 1 shows the gait characteristics of Npc1 mice. These mice showed significantly improved gait compared to their untreated littermates. In fact, they + / + They showed similar walking characteristics to mice.

[0138] Motor function analysis Analysis at 8 weeks of age showed that Npc1 - / - mice and wild-type (Npc1 + / + ) mice, there was no difference in motor function characteristics between the two mice (data not shown).

[0139] However, by 9 weeks of age, deficits in motor coordination became apparent.

[0140] The results of the motor function analysis at 9 weeks of age are shown in Figure 4. Center rearing, activity, rearing, and front-to-back (FR) counts are shown in Figure 4A-4D, respectively. Active time, mobile time, rearing time, and total manual rearing counts are shown in Figure 4E-4H, respectively. Data are expressed as mean ± SEM. Npc1+ / + n=3 for untreated (naive), Npc1 + / + n=2 for treatment, Npc1 - / - n = 1 for untreated (untreated) (hence no statistical analysis), Npc1 - / - n=3 for treatment (treatment).

[0141] The first bar in each graph represents the wild type (Npc1 + / + ) Shows the motor function characteristics of mice.

[0142] The second bar in each graph represents wild-type (Npc1) cells treated with acetyl-DL-leucine. + / + ) The motor function characteristics of mice were not significantly different between these mice and their untreated (naive) littermates.

[0143] The third bar in each graph is Npc1 - / - The mouse exhibits the motor function characteristics of Npc1 mice. + / + Compared to mice, rats exhibited poor motor function, spending very little, if any, time rearing (panel H), particularly with no support of the hind legs (panel A).

[0144] The fourth bar in each graph represents Npc1 treated with acetyl-DL-leucine. - / - The motor function characteristics of Npc1 mice are shown. These mice showed significantly improved motor function compared to their untreated littermates. In fact, they + / + They showed motor function characteristics similar to those of mice.

[0145] lifespan Npc1 - / - It was also observed that treatment of mice with acetyl-DL-leucine (0.1 g / kg from 3 weeks of age) was associated with a statistically significant increase in lifespan (Figure 5). This data further demonstrates the effectiveness of acetyl-leucine in delaying the onset of disease.

[0146] conclusion Npc1 - / - Npc1 mice treated with acetyl-DL-leucine from weaning onwards had discernible signs of illness that distinguished them from their wild-type littermates at 5-6 weeks of age. - / - Littermates did not show such signs until more than two weeks later. - / - Treatment of mice delayed the onset and progression of NPC symptoms and showed evidence of neuroprotection.

[0147] Experimental Example 2 method Fibroblast cell lines derived from NPC patients were treated with N-acetyl-DL-leucine (1 mM) for 3 days, and relative lysosomal mass was quantified via LysoTracker, a fluorescent dye that accumulates in acidic organelles. Increased LysoTracker fluorescence indicates an increase in lysosome size and / or number, a hallmark of NPC cells.

[0148] Furthermore, fibroblasts from patients with Niemann-Pick A (NPA), mucolipidosis type II (MLII), mucopolysaccharidosis type IIIB (MPS IIIB), aspartylglucosaminuria, mucolipidosis type IIIA (MLIIIA), and mucopolysaccharidosis type VII (MPS VII) were treated with acetyl-DL-leucine (1 mM) for 6 days, and lysosomal content was quantified by LysoTracker.

[0149] result Treatment of fibroblasts from NPC patients with mild clinical severity with 1 mM N-acetyl-DL-leucine was associated with a significant decrease in LysoTracker fluorescence, indicating reduced lysosomal mass over time (Figure 6A). These findings were replicated in fibroblasts obtained from additional NPC patients with variable clinical severity who were treated with 1 mM N-acetyl-DL-leucine for 72 hours (Figure 6B).

[0150] Fibroblasts derived from NPA, MLII, MPS IIIB, aspartylglucosaminuria, MLIIIA, and MPS VII patients were observed to have elevated LysoTracker fluorescence levels relative to age-matched wild-type controls (Figures 6C-6H), indicating enlarged lysosomes resulting from lipid accumulation compared to fibroblasts from healthy individuals. Treatment with acetyl-leucine was associated with a statistically significant decrease in LysoTracker fluorescence toward control levels in NPA, MLII, and MPS IIIB fibroblasts relative to untreated NPA, MLII, and MPS IIIB fibroblasts (Figures 6C-6E), but it was associated with a trend toward decreased LysoTracker fluorescence toward control levels in aspartylglucosaminuric, MLIIIA, and MPS VII fibroblasts compared to untreated aspartylglucosaminuric, MLIIIA, and MPS VII fibroblasts, respectively (Figures 6F-6H). The decrease in LysoTracker fluorescence indicated a decrease in lysosomal mass (Figures 6C-6H). Data presented in Figures 6A-6D show the results of treatment for each cell line, with lysosomal mass expressed as a fold change relative to untreated wild-type fibroblasts. Asterisks (* / ****) indicate p-values ​​(<0.05 / 0.001) relative to untreated (untreated) diseased fibroblasts.

[0151] conclusion N-acetyl-DL-leucine treatment was associated with the correction of disturbed lysosomal storage by reducing lysosomal mass, thus directly correcting the phenotype of these lysosomal storage disorders. These diseases represent distinct classes of LSDs, and these results further support the usefulness of acetyl-leucine's effects on a wide range of lysosomal storage disorders.

[0152] Experimental Example 3 Sandhoff disease is a disease that may result from autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. As a result, GM2 ganglioside cannot be degraded and accumulates in lysosomes within cells of the peripheral and central nervous system (CNS).

[0153] This study used a mouse model of Sandhoff disease, Hexb, as described in Jeyakumar et al. - / - Mice were used (Jeyakumar, M et al. (1999) Proc. Natl. Acad. Sci. USA 96:6388-6393).

[0154] Wild type (Hexb + / + ) mice were used as controls.

[0155] lifespan Treatment with acetyl-DL-leucine was associated with a statistically significant increase in the lifespan of Sandhoff mice (Figure 7A). In Figure 7A, acetyl-leucine-treated mice were treated with 0.1 g / kg of acetyl-leucine from 3 weeks of age. An asterisk (*) indicates a p-value of <0.05 versus untreated Sandhoff mice. Data are the mean of n=6 mice per group. Without treatment, the median survival time of Sandhoff mice was 112 days. Treatment with acetyl-leucine (0.1 g / kg body weight from 3 weeks of age onwards) increased the median lifespan to 120 days.

[0156] motor function Treatment of Sandhoff mice with acetyl-leucine resulted in improvements in motor function as shown by bar-crossing and step-cycle studies.

[0157] Bar Crossing Test The bar-crossing test is a method for assessing motor function in mice, which are suspended from the center of a horizontal bar by their forelimbs. Wild-type mice with normal motor function are able to engage their hind limbs and thereby move onto one of the platforms at either end of the bar, thus completing the test.

[0158] Untreated (untreated) Sandhoff mice are able to complete the test until approximately 11 weeks of age, after which point motor function and hindlimb mobility / engagement deteriorate to the point where the mice are unable to complete the test and will fall off the bar onto the padded surface below.

[0159] Treatment of a mouse model of Sandhoff disease with acetyl-DL-leucine (0.1 g / kg body weight from 3 weeks of age) was associated with improved motor function and hindlimb mobility / engagement, as assessed by the bar-crossing test (Figure 7B). In Figure 7B, acetyl-leucine treatment was provided at 0.1 g / kg body weight from 3 weeks of age. Acetyl-leucine-treated Sandhoff disease mice retained the ability to complete the test up to and including 13 weeks of age. Data shown are the average of six mice per group. Treated Sandhoff disease mice retained the ability to complete the test up to and including 13 weeks of age.

[0160] Step Cycle A step cycle is the length of time it takes for a limb to move from the moment it leaves the ground until the next time it leaves the ground.

[0161] Step cycle time was assessed at 12 weeks of age in untreated and acetyl-leucine-treated Sandhoff disease model mice. Treatment consisted of 0.1 g acetyl-leucine / kg body weight starting at 3 weeks of age.

[0162] Treatment of a mouse model of Sandhoff disease with acetyl-leucine was associated with significantly faster front step cycle times (p<0.05 vs. untreated SH mice), significantly faster hind step cycle times (p<0.01 vs. untreated SH mice), and significantly faster average step cycle times (p<0.001 vs. untreated SH mice) (Figure 7C). In Figure 7C, 0.1 g / kg body weight of acetyl-leucine treatment was provided starting at 3 weeks of age. The front step cycle refers to the mouse's forelimbs, the hind step cycle refers to the mouse's hindlimb, and the average step cycle takes into account all limbs of the mouse. Asterisks (* / ** / ***) indicate p-values ​​of <0.05, 0.01, and 0.001 relative to untreated Sandhoff disease mice. Data shown are means ± standard deviations.

[0163] Thus, acetyl-leucine treatment was associated with a faster step cycle in a mouse model of Sandhoff disease, which may indicate an improvement in motor function.

[0164] conclusion These studies demonstrate that acetyl-leucine treatment of a mouse model of Sandhoff disease may result in a significantly increased lifespan as well as improvements in motor function as assessed by two independent experiments.

[0165] Example 4 GM2 gangliosidoses are a group of lysosomal storage disorders resulting from defects in β-hexosaminidase activity, including Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease.

[0166] Fibroblasts from GM2 patients (Tay-Sachs, Sandhoff, and the AB variant of Tay-Sachs) and healthy controls were treated with acetyl-DL-leucine (1 mM for 6 days) before extraction and quantification of glycosphingolipid (GSL) levels by high-performance liquid chromatography (HPLC).

[0167] In the absence of treatment, fibroblasts derived from all three types of GM2 gangliosidosis showed elevated GSL levels compared with untreated wild-type controls. In all three cases, treatment with acetyl-DL-leucine (1 mM for 6 days) was associated with a decrease in GSL accumulation. In the case of Tay-Sachs disease, this decrease was statistically significant (p<0.05). In the cases of Sandhoff disease and the AB variant of Tay-Sachs disease, there was a trend toward treatment-associated decreased GSL levels. Data presented in Figures 8A-8C show the results of treatment for each cell line, expressed as fold change relative to levels in untreated wild-type fibroblasts and with GSL levels adjusted for protein content, respectively.

[0168] Experimental Example 5 patient 1 The patient in this case study was a 28-year-old man with a genetic diagnosis of Tay-Sachs disease who presented with dysarthria, tremor, ataxia of stance and gait, paraplegia, and muscle atrophy. Specifically, the patient was unable to stand or walk, taking steps with strong support, and had distinct postural instability, ocular movement disorder, dysphagia and dysarthria, and mild cognitive dysfunction. The first symptoms were observed at age 16.

[0169] Before treatment began, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5 / 40. Additionally, the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis showed the following results: Average 8 Meter Walk Test (8MW): 21.6 seconds MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 48.3 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 44.9 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 20 Montreal Cognitive Assessment (MoCA): 18 / 30 (Montreal Cognitive Assessment)

[0170] Videos of the patients were also recorded for later comparison.

[0171] The day after this examination, the patient was started on treatment with acetyl-leucine at a dose of 3 g per day for the first week, then 5 g per day from the second week onwards.

[0172] After one and four months, respectively, the patient was re-examined while continuing treatment. After one month, the patient had improved fine motor skills and reduced hand tremor, for example, while eating or drinking. Walking was not significantly different. After four months, the patient was in a stable state with slightly improved cognitive function, but showed deterioration in stance, gait, and fine motor function. The patient's SARA score and the results of the patient's SCAFI analysis compared to baseline are shown below.

[0173] [Table 1]

[0174] Overall, patients showed improvement in symptoms after acetyl-leucine treatment.

[0175] patient 2 The patient in this case study was a 32-year-old woman with a genetic diagnosis of Tay-Sachs disease who presented with ataxia of stance and gait, fine motor impairment, paraparesis of lower extremities, and muscle atrophy. In particular, walking was impossible without support, and the patient suffered from dysphagia, speech disorder, ocular movement disorder, and mild cognitive impairment. The first symptoms were observed at age 7.

[0176] Before treatment began, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 10.5 / 40. Additionally, the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis showed the following results: Average 8 Meter Walk Test (8MW): 12.5 seconds (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 21.5 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 35.5 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 18 Montreal Cognitive Assessment (MoCA): 21 / 30 (Montreal Cognitive Assessment)

[0177] Videos of the patients were also recorded for later comparison.

[0178] On the day of the examination, patients began treatment with acetyl-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week and beyond.

[0179] One month later, the patient was re-examined while continuing treatment and showed increased enunciation, improved postural stability, and enhanced cognitive function. Stance and gait were possible without support. The patient's SARA score and the results of the patient's SCAFI analysis are shown below compared to baseline.

[0180] [Table 2]

[0181] patient 3 The patient in this case study was an 8-year-old male genetically diagnosed with Tay-Sachs disease who had epileptic cramps (tonic-clonic, approximately 10 seconds, self-limiting) almost daily before falling asleep, ocular movement disorder, anarthria, and distinct problems in cognitive function and concentration (neurological examination was not possible), but was very limited in daily activities (unable to feed, wash, or dress himself). The first symptoms were observed at the age of 9 months.

[0182] Prior to initiating treatment, the patient's examination showed a Scale for Assessment and Rating of Ataxia (SARA) score of 36 / 40, an mRDS score of 18 / 24, an EQ-5D-5L visual scale of 50, and an 8MWT (only with strong support) of 18.1.

[0183] Patients began treatment with acetyl-leucine at a dose of 1.5 g per day for the first week, followed by a dose of 3 g per day for the second week and beyond.

[0184] One month later, while continuing treatment, the patient was re-examined and showed increased fine motor skills (able to grasp small objects), increased motivation (attempted to walk independently more frequently), improved postural stability, gait and stance, and was able to utter one word. The patient's SARA, mRDS, EQ-5D-5L visual scale, and 8MWT scores are shown below compared to baseline.

[0185] [Table 3]

[0186] Example 6 The patient in this case study was a 13-year-old male with a genetic diagnosis of GM1 gangliosidosis who was unable to stand or walk independently and had very limited daily activities, but who also had ocular movement disorder, anarthria, and obvious problems with cognitive function and concentration (neurological examination was not possible). The first symptoms were observed at age 2 years.

[0187] Before starting treatment, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 35 / 40, an mRDS score of 15, and an EQ-5D-5L visual scale of 50.

[0188] Patients began treatment with acetyl-leucine at a dose of 1.5 g per day for the first week, followed by a dose of 3 g per day for the second week and beyond.

[0189] One month later, the patient was re-examined while continuing treatment and showed stable general condition, increased gait (slower), and stable stance in a neutral position. The patient's SARA, mRDS, and EQ-5D-5L visual scale scores, compared to baseline, are shown below.

[0190] [Table 4]

[0191] Example 7 The severity of NPC patients may be quantified by assessing various disease parameters and assigning a clinical severity score (CSS), which gives each parameter a score out of 5 (higher scores = higher severity). See Yanjanin et al., "Linear Clinical Progression in Niemann-Pick Disease Type C, Independent of Age of Onset," Am J Med Genet Part B 153B:132-140. Because disease progression appears linear in untreated patients, it is typically possible to predict how an individual's CSS will change over time. For example, if patient A moves from a CSS of 8 to a CSS of 12 between months 0 and 12, it can be predicted that by month 36, the patient will have a CSS of 20. The annual severity increment score (ASIS) quantifies the annual rate of change in CSS, calculated by dividing the patient's CSS by the patient's age. For example, if untreated (untreated) patient B has a CSS of 8 at age 2, the patient's ASIS will be 4. Each year the patient is expected to progress by 4 CSS points, so that at age 4, the patient's CSS will be 16. If therapeutic intervention slowed or prevented disease progression, the patient would be expected to have a lower ASIS score after such treatment than at baseline.

[0192] Ten NPC patients received acetyl-leucine at 4.5 g / day for a long period of time. CSS was determined at baseline and at various time points for eye movement, ambulation, speech, swallowing, fine motor skills, cognition, memory, and seizures. Total CSS was calculated at baseline and each such time point by adding the individual CSS values ​​for each parameter (eye movement, ambulation, etc.). As shown in Table 5, the number of days after treatment initiation at which CSS was assessed varied for each patient.

[0193] [Table 5]

[0194] Tables 6-14 below show the CSSs for overall, eye movement, ambulation, speech, swallowing, fine motor skills, cognition, memory, and seizures, respectively.

[0195] [Table 6]

[0196] [Table 7]

[0197] [Table 8]

[0198] [Table 9]

[0199] [Table 10]

[0200] [Table 11]

[0201] [Table 12]

[0202] [Table 13]

[0203] [Table 14]

[0204] The ASIS at baseline and each time point was calculated using each patient's CSS and age at assessment. The overall ASIS for each patient at each time point is shown in Table 15.

[0205] [Table 15]

[0206] As shown in Table 6 and Figure 9A, none of the 10 patients showed an overall increase in CSS over the course of the study. Patient 6 showed an increased CSS between baseline and time point 2, but returned to baseline by time point 3 and remained there at time point 4. Four of the 10 patients (patients 2, 5, 6, and 7) had a constant CSS over the course of the study, indicating that the disease did not progress in these individuals. Six of the 10 patients (patients 1, 3, 4, 8, 9, and 10) showed a decrease in CSS over the course of the study, indicating that the disease did not progress and, in fact, became less severe. Improvements were seen in different subscores. Patient 1: ambulation, Patient 3: fine motor skills, Patient 4: ambulation and speech, Patient 8: eye movement and fine motor skills, Patient 9: memory, and Patient 10: cognition. Data presented in Figures 10A-10J show the CSS subscores for each patient in the form of bar graphs.

[0207] As shown in Table 15 and Figure 9B, all 10 patients showed a decrease in ASIS during treatment relative to the ASIS at baseline. In patients 2, 5, 6, and 7, as age increased, CSS remained the same, resulting in a slight decrease in ASIS. In patients 1, 3, 4, 8, 9, and 10, as age increased, the decrease in CSS was accompanied by a greater decrease in ASIS. [1] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for treating a lysosomal storage disease (LSD) in a subject in need thereof, or one or more symptoms associated with an LSD, where the LSD is not Niemann-Pick disease type C. [2] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method according to claim 1, wherein the LSD is selected from glycogen storage diseases, mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, lipidoses, sphingolipidoses, and lysosomal transport diseases. [3] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method of [1] above, wherein the LSD is selected from the group consisting of a primary lysosomal hydrolase deficiency, a lysosomal enzyme post-translational processing deficiency, a lysosomal enzyme transport deficiency, a lysosomal enzyme protection deficiency, a soluble non-enzymatic lysosomal protein deficiency, a transmembrane (non-enzymatic) protein deficiency, and an unclassified deficiency. [4] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method of claim 1, wherein the LSD is selected from Tay-Sachs disease, Tay-Sachs AB variant, Sandhoff disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Fabry disease, neuronal ceroid lipofuscinosis, Krabbe disease, Farber disease, Gaucher disease, metachromatic leukodystrophy, multiple sulfatase deficiency, mucolipidosis II, mucolipidosis III, MPS III, MPS VII, GM1 gangliosidosis, and aspartylglucosaminuria. [5] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method of claim 1, wherein the LSD is selected from Tay-Sachs disease, Tay-Sachs AB variant, Sandhoff disease, Niemann-Pick disease type A, mucolipidosis II, mucolipidosis III, MPS III, MPS VII, GM1 gangliosidosis, and aspartylglucosaminuria. [6] 10. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of treating LSD in a subject in need thereof, wherein the subject is asymptomatic. [7] 10. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method of claim 6, wherein the subject has been found to have genetic and / or biochemical markers for LSD. [8] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of delaying the onset of LSD or one or more symptoms of LSD that would otherwise be expected to manifest with typical disease progression. [9] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for treating LSD or one or more symptoms associated with LSD in a subject in need thereof, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[10] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for slowing the progression of LSD or one or more symptoms associated with LSD over time relative to typical disease progression, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[11] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for reversing the progression of LSD or one or more symptoms associated with LSD over time, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[12] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for improving biochemical markers of LSD over time in a subject in need thereof, the method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[13]

[0023] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method according to

[12] above, wherein the biochemical marker is increased lysosomal mass.

[14] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods of [1] to

[13] above, comprising starting administration of a therapeutically effective amount of acetyl-leucine to a subject in need thereof when the subject is asymptomatic.

[15] 14. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method of claim 13, wherein the initial administration occurs after the subject has been found to have genetic and / or biochemical markers for LSD.

[16] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods [1] to [8] above, which comprises administering a therapeutically effective amount of acetyl-leucine to a subject in need thereof for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

[17]

[17] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods according to [1] to

[16] above, wherein the acetyl-leucine is acetyl-DL-leucine.

[18]

[16] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods of [1] to

[16] above, wherein the acetyl-leucine has an enantiomeric excess of the L-enantiomer or the D-enantiomer.

[19]

[16] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods described above in [1] to

[16] , wherein the acetyl-leucine is in a single enantiomeric form, either the L-enantiomer or the D-enantiomer.

[20]

[19] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method according to

[19] above, wherein the single enantiomeric form is the L-enantiomer. [twenty one]

[0023] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods [1] to [8] above, comprising administering acetyl-leucine to a subject in need thereof in a therapeutically effective amount of about 1 g to about 15 g per day, about 1 g to about 10 g per day, about 1.5 g to about 7 g per day, about 4 g to about 6 g per day, or about 4 g to about 5 g per day. [twenty two] The therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods [9] to

[16] above is about 1 g to about 15 g per day, about 1 g to about 10 g per day, about 1.5 g to about 7 g per day, about 4 g to about 6 g per day, or about 4 g to about 5 g per day. [twenty three]

[0023] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods described above in [6] to

[13] , wherein the LSD is selected from glycogen storage diseases, mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, lipidoses, sphingolipidoses, and lysosomal transport diseases. [twenty four]

[0023] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods described above in [6] to

[13] , wherein the LSD is selected from primary lysosomal hydrolase deficiencies, lysosomal enzyme post-translational processing deficiencies, lysosomal enzyme trafficking deficiencies, lysosomal enzyme protection deficiencies, soluble non-enzymatic lysosomal protein deficiencies, transmembrane (non-enzymatic) protein deficiencies, and unclassified deficiencies. [twenty five] 13. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods described above in [6] to

[13] , wherein the LSD is selected from Niemann-Pick disease type C, Tay-Sachs disease, Tay-Sachs disease AB variant, Sandhoff disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Fabry disease, neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis, Farber disease, Gaucher disease, metachromatic leukodystrophy, multiple sulfatase deficiency, mucolipidosis II, mucolipidosis III, MPS III, MPS VII, GM1 gangliosidosis, and aspartylglucosaminuria.

[26]

[0023] 1. The method of claim 1, wherein the LSD is selected from Niemann-Pick disease type C, Tay-Sachs disease, Tay-Sachs AB variant, Sandhoff disease, Niemann-Pick disease type A, mucolipidosis II, mucolipidosis III, MPS III, MPS VII, GM1 gangliosidosis, and aspartylglucosaminuria.

[27] 1. Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for reducing the severity of or eliminating one or more symptoms associated with LSD or reducing the severity of LSD in a subject in need thereof, wherein the LSD is not Niemann-Pick disease type C.

[28] Acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for providing neuroprotection in a subject having, suspected of having, or at risk of having LSD, the method comprising administering a therapeutically effective amount of acetyl-leucine to the subject for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

Claims

1. 1. A pharmaceutical composition for treating a lysosomal storage disease (LSD) or one or more symptoms caused by a LSD in a subject in need thereof, comprising: acetyl-leucine or a pharmaceutically acceptable salt thereof administered to a subject in a therapeutically effective amount for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years; the LSD is selected from Niemann-Pick disease type C, Tay-Sachs disease, Tay-Sachs disease type AB, Sandhoff disease, mucolipidosis II, mucolipidosis IIIA, GM1 gangliosidosis, and aspartylglucosaminuria; The subject achieves an improved Scale of Assessment and Rating of Ataxia (SARA) compared to before administration.

2. 1. A pharmaceutical composition for slowing the progression of a lysosomal storage disease (LSD) or one or more symptoms caused by a LSD in a subject in need thereof relative to typical disease progression, comprising: acetyl-leucine or a pharmaceutically acceptable salt thereof administered to a subject in a therapeutically effective amount for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years; the LSD is selected from Niemann-Pick disease type C, Tay-Sachs disease, Tay-Sachs disease type AB, Sandhoff disease, mucolipidosis II, mucolipidosis IIIA, GM1 gangliosidosis, and aspartylglucosaminuria; The subject achieves an improved Scale of Assessment and Rating of Ataxia (SARA) compared to before administration.

3. 1. A pharmaceutical composition for reversing over time the progression of a lysosomal storage disease (LSD) or one or more symptoms caused by a LSD in a subject in need thereof, comprising: acetyl-leucine or a pharmaceutically acceptable salt thereof administered to a subject in a therapeutically effective amount for a period selected from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years; the LSD is selected from Niemann-Pick disease type C, Tay-Sachs disease, Tay-Sachs disease type AB, Sandhoff disease, mucolipidosis II, mucolipidosis IIIA, GM1 gangliosidosis, and aspartylglucosaminuria; The subject achieves an improved Scale of Assessment and Rating of Ataxia (SARA) compared to before administration.

4. 2. The pharmaceutical composition of claim 1, wherein the acetyl-leucine is acetyl-DL-leucine.

5. 2. The pharmaceutical composition of claim 1, wherein the acetyl-leucine has an enantiomeric excess of the L-enantiomer or the D-enantiomer.

6. 2. The pharmaceutical composition of claim 1, wherein the acetyl-leucine is in a single enantiomeric form, either the L-enantiomer or the D-enantiomer.

7. 7. The pharmaceutical composition of claim 6, wherein the single enantiomeric form is the L-enantiomer.

8. 10. The pharmaceutical composition of claim 1, comprising a therapeutically effective amount of acetyl-leucine of about 1 g to about 15 g per day.

9. 2. The pharmaceutical composition according to claim 1, wherein the LSD is Niemann-Pick disease type C.

10. 10. The pharmaceutical composition of claim 9, comprising a therapeutically effective amount of acetyl-leucine selected from about 1 g to about 10 g per day, about 1.5 g to about 7 g per day, about 4 g to about 6 g per day, or about 4 g to about 5 g per day.

11. 2. The pharmaceutical composition of claim 1, wherein the LSD is selected from Tay-Sachs disease, Sandhoff disease, Niemann-Pick type C, mucolipidosis II, and GM1 gangliosidosis.

12. 10. The pharmaceutical composition of claim 1, wherein the subject achieves at least a one-point improvement in the SARA assessment compared to before administration.

13. 10. The pharmaceutical composition of claim 1, wherein the subject achieves improvement in one or more assessments selected from the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), and the EuroQol 5Q-5D-5L (EQ-5D-5L) questionnaire compared to before administration.

14. 3. The pharmaceutical composition of claim 2, wherein the therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof is in the range of about 1 g to about 15 g per day.

15. 3. The pharmaceutical composition of claim 2, wherein the LSD is selected from Tay-Sachs disease, Sandhoff disease, Niemann-Pick type C, mucolipidosis II, and GM1 gangliosidosis.

16. 3. The pharmaceutical composition of claim 2, wherein the subject achieves an improvement of at least one point in the SARA assessment compared to before administration.

17. 3. The pharmaceutical composition of claim 2, wherein the subject achieves improvement in one or more assessments selected from the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), and the EuroQol 5Q-5D-5L (EQ-5D-5L) questionnaires compared to before administration.

18. 4. The pharmaceutical composition of claim 3, wherein the therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof is in the range of about 1 g to about 15 g per day.

19. 4. The pharmaceutical composition of claim 3, wherein the LSD is selected from Tay-Sachs disease, Sandhoff disease, Niemann-Pick type C, mucolipidosis II, and GM1 gangliosidosis.

20. 4. The pharmaceutical composition of claim 3, wherein the subject achieves an improvement of at least one point in the SARA assessment compared to before administration.

21. 4. The pharmaceutical composition of claim 3, wherein the subject achieves improvement in one or more assessments selected from the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), and the EuroQol 5Q-5D-5L (EQ-5D-5L) questionnaires compared to before administration.

22. 3. The pharmaceutical composition according to claim 2, wherein the LSD is Niemann-Pick disease type C.

23. 4. The pharmaceutical composition according to claim 3, wherein the LSD is Niemann-Pick disease type C.

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