Treatments for neurodegenerative diseases

Abstract

To provide improved and widely applicable treatment methods for neurodegenerative diseases.SOLUTION: The invention employs acetylleucine or a pharmaceutically acceptable salt thereof for use in providing neuroprotection in a subject having, suspected of having, or at risk of having a neurodegenerative disease being cerebellar ataxia, where a therapeutically effective amount of acetylleucine is administered to the subject for a duration selected from at least 1 year, at least 2 years, and at least 5 years.SELECTED DRAWING: Figure 10A

Description

[Technical Field]

[0001] This application claims priority to UK1613829.9 filed on 11 August 2016, UK1702551.1 filed on 16 February 2017, UK1705766.2 filed on 10 April 2017, and UK1706867.7 filed on 28 April 2017, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Neurodegenerative diseases affect neurons. The degenerative process can include progressive loss of neuronal structure, progressive loss of neuronal function, or progressive neuronal cell death. Such progressive neurodegeneration often results in physical disability and mental deterioration. Many neurodegenerative diseases are highly progressive and persistent, and, if any, there are few or no treatment options. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] Although the processes of neurodegeneration are not fully understood, therapeutic agents that have been shown to be widely neuroprotective are generally considered applicable to neurodegenerative diseases. Furthermore, many neurodegenerative diseases are associated with lysosomal dysfunction. This includes both neurodegenerative lysosomal storage disorders (LSDs) and many other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, in which a link to lysosomal defects has been suggested.

[0004] The present disclosure addresses the need to develop improved and widely applicable treatments for neurodegenerative diseases. In particular, the present disclosure describes acetyl-leucine for treating neurodegenerative diseases or one or more symptoms of neurodegenerative diseases in a subject. A neurodegenerative disease may or may not be associated with lysosomal dysfunction.

[0005] In one embodiment, where the neurodegenerative disease is not cerebellar ataxia or Niemann-Pick Type C disease, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of treating (treating) a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease in a subject in need thereof.

[0006] In one embodiment of the present disclosure, where the subject is asymptomatic, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of treating (treating) a neurodegenerative disease in a subject in need thereof.

[0007] In another embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of delaying the onset of symptoms of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to appear according to the progression of a typical disease.

[0008] In yet another embodiment , acetyl-leucine or a pharmaceutically acceptable salt thereof is included for use in a method of treating (treating) a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of acetyl-leucine 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.

[0009] In one embodiment, the present disclosure describes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of delaying the progression of a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease over time as compared to the progression of a typical disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of acetyl-leucine for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years. <> <>

[0010] <> In a further embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of reversing over time the progression of a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of acetyl-leucine for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years. <> <>

[0011] <> In another embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof is disclosed for use in a method of improving over time a biochemical marker of a neurodegenerative disease in a subject in need thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of acetyl-leucine for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years. <> <>

[0012] <> In another embodiment, the present disclosure comprises acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of reducing the severity of a neurodegenerative disease or reducing or eliminating the severity of one or more existing symptoms associated with a neurodegenerative disease in a subject in need thereof, where the neurodegenerative disease is not spinocerebellar ataxia or Niemann-Pick disease type C. <> <>

[0013] <> In further embodiments, the disclosure includes acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method for providing neuroprotective effects in subjects having, suspected of having, or potentially having a neurodegenerative disease, wherein the method comprises administering a therapeutically effective amount of acetyl-leucine to a 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.

[0014] Further embodiments of this disclosure include acetylleucine or a pharmaceutically acceptable salt thereof for use in a method for delaying the progression of neurodegenerative disease or lysosomal storage disorder (LSD) in a subject. Another embodiment includes acetylleucine or a pharmaceutically acceptable salt thereof for use in a method for providing neuroprotective effects in a subject having neurodegenerative disease or LSD. In one embodiment, acetylleucine is in the form of a racemic compound with an enantiomeric excess of the L-type optical isomer (enantiomer). In another embodiment, the method further includes administering acetylleucine in doses between 1.5 g and 10 g per day. Furthermore, in one embodiment, the method includes administering acetylleucine for a treatment period of two weeks or longer. For example, the method includes administering acetylleucine or a pharmaceutically acceptable salt thereof before the onset of symptoms of the disease or disorder to be treated. In further embodiments, the method further comprises administering another therapy or agent intended to prevent or treat the disease or disorder to be treated. In one embodiment of the present disclosure, a kit for delaying the progression of a neurodegenerative disease or LSD in a subject, the kit comprising means for diagnosing or predicting the neurodegenerative disease or LSD, and acetyl-leucine or a pharmaceutically acceptable salt thereof. For example, the kit comprises means for diagnosing or predicting the neurodegenerative disease or LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof. In one further embodiment of the present disclosure, the use of acetyl-leucine or a pharmaceutically acceptable salt thereof as a neuroprotective agent in a subject having a neurodegenerative disease or LSD is provided. In further embodiments of the method, kit, or use, the neurodegenerative disease is associated with defects in lysosome accumulation. In one example of the method, kit, or use, neurodegenerative diseases include alcoholism, Alexander's disease, Alper's disease, and Alzheimer's disease.Diseases such as amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, neuronal ceroid lipofuscinoses, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, and Lewy body dementia. Dementia, neuroborreliosis, Machado-Joseph disease, multiple system atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidoses, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pick's disease, Pompe disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum's disease, Schilder's diseaseThese include disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis. In the method, kit, or further examples of use, LSD is used for Niemann-Pick disease type C (NPC1 and / or NPC2 deficiency), Smith-Lemli-Opitz syndrome (SLOS), congenital malformations of cholesterol synthesis, Tangier disease, Pelizaeus-Merzbacher disease, neuronal ceroid lipofuscinosis, primary glycosphingolipidosis, Farber disease, or multiple sulfatase deficiency. For example, in the method, kit, or use, primary sphingoglycolipidosis is Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease, or metachromatic leukodystrophy (MLD). Furthermore, for example, in the method, kit, or use, LSD is NPC, Tay-Sachs diseaseThese include diseases such as 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 IV, MPS IV A, MPS IV B, MPS VI, MPS VII, MPS IX, diseases involving secondary lysosomes, SLOS, or Tangier disease. In the method, the kit, or additional examples of its use, neurodegenerative diseases include cerebellar ataxia, Niemann-Pick disease, Parkinson's disease, neuronopathic Gaucher disease, Sandhoff's disease, Louis-Barr syndrome, Alzheimer's disease, Parkinson's disease, multiple systems atrophy, fronto-temporal dementia, or lower body Parkinson's syndrome. In further embodiments of the method, the kit, or its use, neurodegenerative diseases include Niemann-Pick disease, Niemann-Pick disease type C, Niemann-Pick disease type A, Sandhoff disease, amyotrophic lateral sclerosis (ALS), multisystemic atrophy cerebellar type (MSA-C), frontotemporal dementia with parkinson's disease, corticobasal degeneration syndrome, progressive supranuclear palsy, or cerebellar nystagmus.In the method, the kit, or one example of its use, LSD is Niemann-Pick disease, Niemann-Pick disease type C, Niemann-Pick disease type A, Taysachs disease, Sandhoff disease, or mucolipidosis type II. [Brief explanation of the drawing]

[0015] Brief explanation of the drawing [Figure 1] Figure 1 shows photographs of treated (Figure 1A) and untreated (Figure 1B) Npc1- / - mice at 9 weeks of age.

[0016] [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, starting from weaning.

[0017] [Figure 3] Figures 3A to 3G show gait analysis data for Npc1- / - mice compared to 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 to 3C, respectively. Figures 3D and 3E show forelimb (FP) data (stand mean and step cycle in panel D; duty cycle in panel E). Figures 3F and 3G show hindlimb (HP) data (stand mean and step cycle in panel F; duty cycle in panel G).

[0018] [Figure 4] Figures 4A to 4H show motor function analysis data of Npc1- / - mice compared to wild-type (Npc1+ / +) mice with and without acetyl-DL-leucine treatment, from weaning. Figures 4A to 4D show center rearing, activity, rearing, and front-to-back (FR) counts, respectively. Figures 4E to 4H show active time, mobile time, rearing time, and total manual rearing count, respectively.

[0019] [Figure 5] Figure 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.

[0020] [Figure 6] Figures 6A and 6B show the decrease in lysosomal volume in non-neuronal NPC cells following treatment with acetyl-DL-leucine. Figures 6C to 6H show the effects of treatment with acetyl-DL-leucine on lysosomal volume in fibroblasts from patients with NPA, MLII, MPS IIIB, aspartylglucosaminuria, MLIIIA, and MPS VII, respectively.

[0021] [Figure 7]Figure 7A shows the survival curves representing mortality rates in untreated and acetyl-leucine-treated wild-type and Sandhoff disease mice. Figure 7B shows the bar crossing scores for untreated and acetyl-leucine-treated Sandhoff disease model mice. Figure 7C shows the step cycle time for untreated and acetyl-leucine-treated Sandhoff mice evaluated at 12 weeks of age.

[0022] [Figure 8] Figures 8A to 8C show the effect of acetyl-DL-leucine treatment on sphingoglycolipid (GSL) levels in fibroblasts of GM2 gangliosidoses patients (Tay-Sachs disease, Sandhoff disease, and AB variant of Tay-Sachs disease, respectively).

[0023] [Figure 9] Figure 9 shows the analysis matrix for a 75-year-old male patient diagnosed with corticobasal degeneration syndrome before and during acetyl-leucine treatment. The pink areas in the matrix indicate improvement compared to the pre-treatment state.

[0024] [Figure 10] Figures 10A and 10B show the time-course effects of acetyl-DL-leucine treatment on the overall clinical severity score (CSS) and overall annual severity increment score (ASIS) of 10 NPC patients, respectively.

[0025] [Figure 11] Figures 11A to 11J show the time course of acetyl-DL-leucine treatment on the CSS subscore of each of the 10 NPC patients.

[0026] [Figure 12] Figures 12A and 12B show the effects of acetyl-DL-leucine treatment of wild-type NPC1- / - mice on the levels of amyloid precursor protein C-terminal fragments (APP-CTFs) and microtubule-associated protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate, respectively.

[0027] [Figure 13] Figures 13A to 13C show that patients diagnosed with lower eyelid nystagmus syndrome were able to partially suppress nystagmus by fixation after treatment with acetyl-DL-leucine. [Modes for carrying out the invention]

[0028] Description Acetyl-leucine (acetyl-DL-leucine) and its salts, in racemic form, are effective in treating dizziness from various origins, particularly dizziness associated with Meniere's disease and dizziness of inflammatory (vestibular neuritis) or toxic origins. For example, acetyl-leucine is marketed as an anti-dizziness agent in racemic form by Pierre Fabre Medicament under the trade name Tanganil®. Clinical results of Tanganil® reported by various authors show improvement in dizziness symptoms in over 95% of cases, including the disappearance of dizziness attacks.

[0029] Acetyl-DL-leucine has been used in France since 1957 to treat acute vertigo and has an excellent safety profile; however, its safety in chronic use remains undetermined. Despite numerous hypotheses, including membrane potential stabilization, the pharmacological and electrophysiological modes of its action remain unclear. (Vibert et al (2001) Eur J Neurosci; 13(4):735-48; Ferber-Viart et al (2009) Audio 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 symptoms of cerebellar ataxia using acetyl-DL-leucine was demonstrated in a case series involving cerebellar patients (Strupp et al (2013) J Neurol; 260(10):2556-61). Another case series did not find any benefit (Pelz et al (2015) J Neurol; 262(5):1373-5). Quantitative gait analysis showed that acetyl-DL-leucine improved transient gait variability in patients with cerebellar ataxia (Schniepp et al (2015) Cerebellum; 3:8). A one-month study involving 12 patients with Niemann-Pick disease type C (NPC) showed improvement in ataxic symptoms (Bremova et al (2015) Neurology; 85(16):1368-75).Furthermore, PET studies in patients with ataxia who received acetyl-DL-leucine showed increased metabolism in the midbrain and lower brainstem of the responders (Becker-Bense et al (2015) Abstract EAN).

[0030] However, acetyl-leucine is not known to treat neurodegenerative diseases, which generally progress over several years to decades. Surprisingly, this disclosure suggests that acetyl-leucine, or any pharmaceutically acceptable salt thereof, may be used in a manner that treats neurodegenerative diseases in subjects requiring it, by slowing or reversing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease, for example, over a long period compared to typical disease progression, and / or delaying the signs of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest due to typical disease progression. These exemplary uses in this disclosure, and the others described herein, were not anticipated at all, so no such benefits were observed, nor could they be inferred from prior art teachings. As demonstrated by experimental examples showing efficacy across a wide range of neurodegenerative diseases, the inventors believe that acetyl-leucine acts as a neuroprotective agent, inhibiting neurodegeneration that would otherwise be expected to manifest. In addition, many neurodegenerative diseases are associated with defects in lysosome accumulation, and lysosomal dysfunction, such as abnormally high levels of lysosome accumulation, may be the cause of neuronal dysfunction and neuronal death. As demonstrated by experimental examples, though we do not wish to be constrained by any particular theory, we have found that, among other things, acetyl-leucine can improve cellular dysfunction (for example, by reducing lysosomal volume toward control values) and provide neuroprotective effects.

[0031] Accordingly, this disclosure provides acetyl-leucine or a pharmaceutically acceptable salt thereof for use in methods of treating neurodegenerative diseases or one or more symptoms of neurodegenerative diseases in subjects where such need exists.

[0032] The term "subject" as used herein may be a vertebrate, mammal, or livestock. Accordingly, the compositions provided herein may be used to treat any mammal, for example, livestock (e.g., horse, cattle, sheep, or pig), pet (e.g., cat, dog, rabbit, or guinea pig), laboratory animal (e.g., mouse or rat), or in veterinary applications. In one embodiment, the subject is a human.

[0033] As used herein, “neurodegenerative disease” means any disorder affecting neurons, including progressive loss of neuronal structure, progressive loss of neuronal function, or progressive neuronal cell death.

[0034] As used herein, the singular forms “a,” “an,” and “the” include plural references. The terms “approximately” and “about” mean that, given the nature or precision of the measurement, the number or value referenced is nearly the same as the measured quantity, with an acceptable degree of error.

[0035] As used herein, the terms “approximately” and “about” should generally be understood to encompass ±20% of the specified quantity, frequency, or value. Unless otherwise stated, the quantities expressed herein are approximate, meaning that the terms “about” or “approximately” can be inferred when not explicitly stated.

[0036] As used herein, the terms “administer,” “give,” or “administer” mean (1) supplying, giving, giving, and / or prescribing the compositions relating to this disclosure by a practicing physician or his authorized agent or under his direction, and (2) taking, ingesting, or consuming the compositions relating to this disclosure by a patient or by oneself.

[0037] Even if not explicitly stated, references to "acetyl-leucine" throughout the text include its pharmaceutically acceptable salts.

[0038] Acetyl leucine may be in the form of a racemic compound, meaning that the compound contains approximately equal amounts of enantiomers. Alternatively, it may exist in an enantiomer 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 example, the single enantiomer is the L-enantiomer. The racemic and enantiomer forms may be obtained according to procedures known in the art.

[0039] The “pharmaceutically acceptable salt” as used herein refers to any salt preparation suitable for use in pharmaceutical applications. Without limitation, pharmaceutically acceptable salts include amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, and 1-para-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole. This includes salts of alkali metals such as benzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine, and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, alkali metal salts such as lithium, potassium, and sodium; alkaline earth metal salts such as barium, calcium, and magnesium; transition metal salts such as zinc and aluminum; other metal salts such as sodium hydrogen phosphate and disodium phosphate; mineral acids such as hydrochloride and sulfate; and salts of organic acids such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, and fumarate.

[0040] Acetyl leucine or a pharmaceutically acceptable salt thereof may be prescribed and administered in accordance with teachings known in the art. For example, acetyl leucine or a pharmaceutically acceptable salt thereof may be formulated as a pharmaceutical composition. A pharmaceutical composition may include acetyl leucine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. References to pharmaceutical compositions include the active agent, either alone or in the form of a pharmaceutical composition.

[0041] The pharmaceutical composition may take any of many different forms, particularly depending on the mode in which it is to be used. For example, it may be a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle solution, transdermal patch, liposome suspension, or any other form suitable for administration to a human or animal in need of treatment.

[0042] The “pharmaceutically acceptable carrier” referred to herein is any known compound or combination of known compounds that is known to those skilled in the art to be useful in formulating a pharmaceutical composition. It will be understood that the carrier of the pharmaceutical composition should be tolerable by the subject to which it is given.

[0043] In one embodiment, the pharmaceutically acceptable carrier may be solid, and its composition may be in the form of a powder or a tablet. A solid pharmaceutically acceptable carrier may contain, without limitation, one or more substances that may also function as flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, dyes, bulking agents, flow enhancers, compression aids, inert binders, sweeteners, preservatives, dyes, coating agents, or tablet disintegrants. The carrier may also be an encapsulating material. In powder form, the carrier may be a finely ground solid mixed with the finely ground active agent according to the present invention. In tablet form, the active agent may be mixed in an appropriate proportion with a carrier having the required compressibility properties and then compressed to the desired shape and size. The powder and tablet 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-point waxes, and ion-exchange resins. In another example, the pharmaceutically acceptable carrier may be a gel, and the composition may be in the form of a cream or the like.

[0044] The carrier may contain, without limitation, one or more excipients or diluents. Examples of such excipients include gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcam, and colloidal silicon dioxide.

[0045] In another embodiment, the pharmaceutically acceptable carrier may be a liquid. In one embodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. Acetyl-leucine may be dissolved or suspended in water, organic solvents, a mixture of both, or a pharmaceutically acceptable liquid carrier such as a pharmaceutically acceptable oil. Liquid carriers may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure modifiers. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives such as cellulose derivatives, e.g., sodium carboxymethylcellulose solution), alcohols (including polyhydric and monohydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile solution carriers are useful in compositions in the form of sterile solutions for parenteral administration. Liquid carriers for pressurized compositions may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0046] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, may be administered, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. Active agents may be prepared as sterile solid compositions that may be dissolved or suspended at administration using sterile water, saline, or other suitable sterile injectable media.

[0047] The composition may be administered orally in the form of a sterile solution or suspension containing other solutes or suspensions (e.g., physiological saline or glucose sufficient to make the solution isosmotic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (its anhydrous copolymerized with oleic acid sorbitol and ethylene oxide), etc. The composition may also be administered orally in the form of either a liquid or solid composition. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders, as well as liquid forms such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0048] Acetyl leucine and compositions containing it may instead be administered by inhalation (e.g., intranasally). The compositions may also be formulated for topical use; for example, a cream or ointment may be applied to the skin.

[0049] Acetyl leucine may be incorporated into a sustained-release or delayed-release device. Such a device may, for example, be inserted above or below the skin, and the drug may be released over several weeks or months. Such a device may be advantageous when long-term treatment with acetyl leucine used in accordance with this disclosure is required, and when frequent administration (for example, at least daily) is typically required.

[0050] In one embodiment, the pharmaceutical composition is in the form of a tablet. In the tablet, the active agent may be mixed in an appropriate proportion with a pharmaceutically acceptable vehicle such as a carrier having the required compressibility properties, and then compressed to the desired shape and size. The tablet may contain up to 99% by weight of the active agent.

[0051] 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 tablets.

[0052] Pharmaceutical compositions in solid oral dosage forms, such as tablets, may be prepared by any method known in the field of pharmacy. Pharmaceutical compositions are typically prepared by mixing acetyl-leucine or a pharmaceutically acceptable salt thereof with a conventionally pharmaceutically acceptable carrier.

[0053] The tablets may be formulated as known in the art. Tanganil® includes, for example, wheat starch, pregelatinized corn starch, calcium carbonate, and magnesium stearate as excipients. For example, the same or similar excipients may be used in conjunction with the present disclosure.

[0054] Each 700 mg Tanganil® tablet is composed of the following: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinized corn starch, 13 mg calcium carbonate, and 11 mg magnesium stearate. For example, the same tablet may be used in conjunction with the present disclosure.

[0055] This disclosure describes acetyl-leucine, comprising compositions and methods for treating neurodegenerative diseases or one or more symptoms of neurodegenerative diseases in subjects with a need for such treatment. Subjects with a need may have genetic, biochemical, or other similar identifiable markers for neurodegenerative diseases. For example, markers for neurodegenerative diseases may be cellular markers. Subjects with a need may have been diagnosed with a neurodegenerative disease. For example, a subject may have been diagnosed with a neurodegenerative disease according to genetic, biochemical, or other similar identifiable markers. Subjects with a need may be suspected of having or at risk of having a neurodegenerative disease. For example, a subject may have a genetic predisposition to neurodegenerative diseases (e.g., a subject may have a family member with one or more neurodegenerative diseases). Subjects with a need may be symptomatic (i.e., have one or more symptoms associated with a neurodegenerative disease). Subjects with a need may be asymptomatic. The terms “symptomatic” and “asymptomatic” should be understood to be used in relation to symptoms of neurodegenerative diseases. Subjects with genetic, biochemical, or other similar identifiable markers for neurodegenerative disease, such as subjects diagnosed with a neurodegenerative disease based on genetic, biochemical, or other similar identifiable markers but without further symptoms of the disease, are included in the scope of “asymptomatic” for the purposes of this disclosure.

[0056] As used herein, “treating (managing) a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to occur in accordance with the typical progression of the disease, reducing the severity of a neurodegenerative disease over time or reducing the severity of one or more pre-existing symptoms associated with a neurodegenerative disease, slowing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time compared to the typical progression of the disease, and / or reversing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time. “Treatment (managing) a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” may also mean improving the biochemical markers of a neurodegenerative disease.

[0057] As used herein, “typical disease progression,” “typically expected disease progression,” etc., mean the typical or expected progression of a neurodegenerative disease, one or more symptoms associated with a neurodegenerative disease, or a biochemical marker of a neurodegenerative disease, if the subject is not treated. Typical or expected disease progression may be based on, for example, known scales, indices, ratings, or scores, or other appropriate tests, for assessing the progression of a neurodegenerative disease, one or more symptoms associated with a neurodegenerative disease, or a biochemical marker of a neurodegenerative disease, as disclosed herein as experimental examples. Such scales, indices, ratings, scores, or other appropriate tests may correspond to the progression of the neurodegenerative disease as a whole or the progression of one or more symptoms associated with a neurodegenerative disease. For example, typical or expected disease progression may be based on the typical or expected onset or severity of a neurodegenerative disease, or on symptoms or sets of symptoms associated with a neurodegenerative disease. Typical or expected disease progression may be determined on a case-by-case basis, or it may be based on what is typically experienced or observed in a population of subjects or subpopulations suffering from neurodegenerative diseases. Such subpopulations may include, for example, subpopulations of the same sex, of the same or similar age, and of the same or similar timing for the onset of one or more symptoms.

[0058] In one embodiment, “treating (managing) a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to develop in accordance with the typical progression of the disease. As used herein, “delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means extending the time to the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease, or preventing its onset. For example, the onset can be said to have been delayed if the time to the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease is at least 5% longer than that observed in accordance with the typical progression of the disease. Furthermore, 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. Administration of acetyl-leucine may be initiated when the subject is asymptomatic in order to delay the onset of one or more symptoms of neurodegenerative disease that would otherwise be expected to develop in accordance with the typical progression of the disease. In another embodiment, the subject is symptomatic. Administration of acetyl-leucine may be initiated when the subject has several symptoms in order to delay the onset of one or more additional symptoms of neurodegenerative disease that would otherwise be expected to develop in accordance with the typical progression of the disease. Subjects who need it may continue to receive treatment with acetyl-leucine for the duration described herein. In one embodiment, the treatment prevents the onset of one or more symptoms of neurodegenerative disease that would otherwise be expected to develop in accordance with the typical progression of the disease.

[0059] In one embodiment, “treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means reducing the severity of the neurodegenerative disease or reducing or eliminating the severity of one or more pre-existing symptoms associated with the neurodegenerative disease. The severity of the neurodegenerative disease or the severity of pre-existing symptoms may be assessed using a known scale, index, rating, or score, or another appropriate test for assessing severity, such as those described herein by example. For example, the scale, index, rating, score, or other appropriate test may correspond to the severity of the disease as a whole or the severity of one or more symptoms associated with the disease. In one embodiment, the 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.

[0060] In one embodiment, “treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means delaying the progression of one or more symptoms of a neurodegenerative disease or associated with a neurodegenerative disease over time, or reversing the progression of one or more symptoms of a neurodegenerative disease or associated with a neurodegenerative disease over time, compared to the typical progression of the disease. The duration for which the treatment delays or reverses the progression may coincide with the duration of the treatment as described herein. The treatment may delay or reverse the progression for a period of, 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. The treatment may delay or reverse the progression for a period of, for example, about 3 months or more, about 4 months or more, about 5 months or more, or about 6 months or more. It may slow or reverse the progression of the disease over a period of time, for example, more than one year, two years, three years, four years, five years, or ten years. The treatment may slow or reverse the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease throughout the patient's life.

[0061] In one embodiment, “treating (managing) a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means slowing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time compared to the typical progression of the disease. As used herein, “slowing the progression of one or more symptoms of a neurodegenerative disease or related to a neurodegenerative disease over time” means slowing and / or stopping the progression of the disease or one or more symptoms of the disease (e.g., slowing and / or stopping the worsening or increasing severity of the disease or one or more symptoms of the disease). Disease progression may be determined using known scales, indices, ratings, or scores, or other appropriate tests for assessing progression, such as those described herein as examples. For example, the scales, indices, ratings, scores, or other appropriate tests may correspond to the progression of the disease as a whole or the progression of one or more symptoms related to the disease. In one embodiment, “delaying the progression of a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease” means that the severity value of the disease in question (e.g., overall severity or severity of one or more symptoms), as determined by a known scale, index, rating, etc., or other appropriate test for assessing severity, does not increase significantly (e.g., remains at least substantially constant). In one embodiment, “delaying the progression of a neurodegenerative disease or the progression of one or more symptoms of a neurodegenerative disease” means increasing the time it takes for a subject to reach a severity value (e.g., decreasing the rate of change that increases severity) or preventing the subject from reaching that value, according to a known scale, index, rating, score, etc., or other appropriate test for assessing progression in comparison to a value corresponding to typical disease progression. For example, progression can be said to be delayed if the time to reach a severity value is at least 5% longer than the time observed with typical disease progression.Furthermore, for example, an increase is observed over a period of 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%. The time over which the treatment slows the progression of the neurodegenerative disease or the progression of one or more symptoms of the neurodegenerative disease may coincide with 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. The treatment may slow 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.

[0062] In one embodiment, “treating (managing) a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means reversing the progression of the neurodegenerative disease or one or more symptoms of the neurodegenerative disease over time. As used herein, “reversing the progression of a neurodegenerative disease or the progression of one or more symptoms of a neurodegenerative disease” means stopping the progression of the disease or one or more symptoms of the disease and reducing its severity. The progression and severity of the disease may be determined using a known scale, index, rating, or score, such as those described herein as examples, or another appropriate test for assessing the progression and severity. For example, the scale, index, rating, or score, or other appropriate test, may correspond to the progression and severity of the disease as a whole, or to the progression and severity of one or more symptoms associated with the disease. In one embodiment, “reversing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time” means that the severity value of the disease (e.g., overall severity or severity of one or more symptoms), as determined by a known scale, index, assessment, score, or another appropriate test for assessing severity, improves over time (i.e., shows a decrease in severity over time). The time over which a treatment reverses the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease may coincide with the duration of the treatment as described herein. In one embodiment, the 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 further embodiments, the 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. The treatment may reverse progression over the patient’s lifetime.

[0063] In one embodiment, “treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” means improving a biochemical marker of the neurodegenerative disease in the subject (e.g., secondary biochemical changes resulting from primary accumulation or increased levels of accumulated metabolites). The biochemical marker is a signal of disease activity and may provide an ongoing indicator of disease severity and progression over time. In one embodiment, the biochemical marker is improved in terms of a control value. In one example, the biochemical marker is selected from increased lysosome volume, increased sphingoglycolipid (GSL) levels, increased microtubule-associated protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels, and increased amyloid precursor protein C-terminal fragment (APP-CTF) levels. In one example, the biochemical marker is increased lysosome volume, and the treatment reduces lysosome volume in the subject. In another example, the biochemical marker is increased sphingoglycolipid (GSL) levels, and the treatment reduces GSL levels in the subject. In one example, the biochemical marker was the increased microtubule-binding protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) level, and the treatment reduced LC3-II levels in the subject. In another example, the biochemical marker was the amyloid precursor protein C-terminal fragment (APP-CTF) level, and the treatment reduced APP-CTF levels in the subject. In yet another example, the treatment improved the biochemical marker over time.For example, in one embodiment, improving biochemical markers over time means that the treatment improves the biochemical markers over time toward control values ​​compared to typical disease progression, prevents the progression of biochemical markers over time, and / or slows the progression of biochemical markers over time. The time it takes for the treatment to improve biochemical markers may coincide with the duration of the treatment as described herein. In one embodiment, the treatment improves biochemical markers for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. The treatment improves biochemical markers 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 biochemical markers over the patient's lifetime.

[0064] The “symptoms” of neurodegenerative diseases include, but are not limited to, any clinical or laboratory manifestations associated with neurodegenerative diseases that can be felt or observed by the subject. Symptoms described herein include, without limitation, neurological and psychiatric symptoms. Examples of neurological symptoms include ataxia, hypokinesia, rigidity, tremor, or other motor disorders such as dystonia; central oculomotor disorders such as vertical and horizontal supranuclear saccades / gaze palsy; and neuropsychological disorders such as dementia. Examples of psychiatric symptoms include depression, behavioral disorders, or psychosis. Symptom manifestations may range from birth to adulthood.

[0065] For example, the progression of neurodegenerative diseases over time or in response to treatment can be monitored by comparing the results of one or more known tests at two or more time points. 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), and the Wechsler Intelligence Scale for Children-IV. The progression and / or severity of the disease can be assessed using motor impairments such as the Children's WISC-IV (WISC-IV), the Montreal Cognitive Assessment (MoCA), and the Unified Parkinson's Rating Scale (UPRS) or the Unified Multiple System Atrophy Rating Scale (UMSARS), or other appropriate tests.For certain long-term disorders (LSDs) such as NPC, specific scores have been developed and validated over the past few decades, including the clinical severity score (CSS), the annual severity increment score (ASIS) (see Yanjanin et al., "Linear Clinical Progression Independent of Age of Onset in Niemann-Pick Disease Type C," Am J Med Genet Part B 153B:132-140), and the modified 6-Domain NP-C disability scale (mDRS score). For example, the severity of an NPC patient can be quantified by assigning a CSS, which assesses various parameters of the disease (e.g., gait, seizures, eye movements) and assigns a 5-point score to each parameter. A higher score indicates greater severity. The ASIS quantifies the annual rate of change in CSS, calculated by dividing the CSS by the patient's age. In this regard, certain scores in these tests are characteristic of patients with symptomatic neurodegenerative diseases and demonstrate disease progression and / or severity.

[0066] In this way, for example, “treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease” may be equivalent to achieving an improved assessment, such as the SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and / or MoCA scores described herein, or the results of another appropriate test for characterizing a patient with a neurodegenerative disease. For example, in one embodiment, “reducing the severity of a neurodegenerative disease, or reducing the severity of one or more pre-existing symptoms of a neurodegenerative disease” means improving the results of another appropriate test for assessing severity, such as improving the score or result from a characteristic severity value for a symptomatic subject to a characteristic value for an asymptomatic subject. In another embodiment, “delaying the progression of neurodegenerative disease or the progression of one or more symptoms of neurodegenerative disease” means that the subject’s SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and / or MoCA score, or the result of another appropriate test for assessing progression, does not increase significantly (e.g., remains at least substantially constant). In a further embodiment, “delaying the progression of neurodegenerative disease or the progression of one or more symptoms of neurodegenerative disease” means preventing the subject’s SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and / or MoCA score, or the result of another appropriate test for assessing progression, from reaching a value compared to the value of typical disease progression, or increasing the time it takes to reach such a value.In another embodiment, “reversing the progression of neurodegenerative disease or the progression of one or more symptoms of neurodegenerative disease over time” means that the results of the subject’s SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and / or MoCA score, or another appropriate test for assessing progression, improve over time (i.e., show a decrease in severity over time).

[0067] For example, the mDRS, a four-domain scale (ambulation, manipulation, language, and swallowing), may be applied to assess the overall neurological state. Cerebellar function may be assessed using the SARA, an eight-item clinical rating scale (gait, stance, sitting, speech, fine motor skills, and taxis; ranging from 0 to 40, with 0 being the best neurological state 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 repetitions of "PATA" over 10 seconds. Subjective impairment and quality of life may be assessed using the EQ-5D-5L questionnaire and VAS. To assess eye movement function, three-dimensional videooculography (EyeSeeCam) may be used to measure peak saccade velocity, smooth tracking acquisition, peak slow phase velocity of gaze-evoked nystagmus (gaze-holding ability), peak slow phase velocity of optokinetic nystagmus, and acquisition of the horizontal vestibulo-ocular reflex. To assess cognitive states, WAIS-R or WISC-IV, and MoCA, different cognitive domains, including attention and concentration, executive function, memory, language, visual construction skills, conceptual thinking, calculation, and orientation, may be used, with a maximum score of 30 points and 26 cutoff scores. Those skilled in the art will know how to administer these and other such tests.

[0068] Acetyl leucine, or a pharmaceutically acceptable salt thereof, may be administered in doses such as approximately 500 mg to 15 g per day, or approximately 500 mg to 10 g per day, or approximately 1.5 g to 10 g per day, optionally via solid or liquid oral routes. Acetyl leucine, or a pharmaceutically acceptable salt thereof, may be administered in doses such as 1.5 g to 2 g per day, in 3-4 tablets taken twice a day, in the morning and evening, in the same dosage as Tanganil® prescribed for adults.

[0069] If only one enantiomer is administered, the dose may be reduced accordingly. For example, if only acetyl-L-leucine or only acetyl-D-leucine is administered, the dose may range from approximately 250 mg to 15 g per day, from approximately 250 mg to 10 g per day, or from approximately 250 mg to 5 g per day, for example, from approximately 0.75 g to 5 g per day.

[0070] In one example, the dosage ranges from approximately 1 g to approximately 15 g per day, from approximately 1 g to approximately 10 g per day, or from approximately 1.5 g to approximately 7 g per day. It may be approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 g to approximately 15 g per day. It may be approximately 2, 3, 4, 5, 6, 7, 8, or 9 g to approximately 10 g per day. It may be greater than approximately 1.5 g per day, but less than approximately 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 g per day. In one example, the dosage ranges from approximately 4 g to approximately 6 g per day. In one example, the dosage ranges from approximately 4 g to approximately 5 g per day. In one example, the dosage is approximately 4.5 g per day. In one embodiment, the dose is approximately 5 g per day. In one embodiment, these doses are administered in solid oral dosage form, particularly tablets. In another embodiment, these doses are relative to acetylleucine, when in its racemic form. In the presence of enantiomer excess, the dose relative to acetylleucine may be lower than those listed herein, for example, less than approximately 50%. Thus, the range of the above-mentioned doses when halved is also expressly encompassed by this disclosure.

[0071] The total daily dose can be spread out over multiple doses; that is, administration may be given 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 may be divided into two doses (e.g., morning and evening) or three doses (e.g., morning, noon, and evening). Each dose may be appropriately administered with or without food. For example, acetyl-leucine may be administered about one or two hours before a meal, for example, at least 20 minutes, at least 30 minutes, at least 40 minutes, or at least one hour before a meal, or it may be administered about one, two, or three hours after a meal, for example, waiting at least 20 minutes, at least 30 minutes, at least one hour, at least 1.5 hours, at least two hours, or at least 2.5 hours after a meal. For example, a total daily dose of 4.5 g of acetyl-DL-leucine may be administered as three Tanganil® (or equivalent) tablets before, during, or after breakfast, as well as three more tablets before, during, or after lunch, and as three more tablets before, during, or after dinner.

[0072] Administration of acetyl-leucine under this disclosure may be initiated before or after a subject is found to have a genetic, biochemical, or other similar identifiable marker for neurodegenerative disease, in the former case, when the subject is suspected of having or at risk of having a neurodegenerative disease. Administration may be initiated at or around the time a subject is found to have a genetic, biochemical, or other similar identifiable marker for neurodegenerative disease. Similarly, administration may be initiated before, at or around the time a subject is diagnosed with a neurodegenerative disease, such as before, when, or around the time a subject is found to have a genetic, biochemical, or other similar identifiable marker for neurodegenerative disease, or after such a diagnosis. Administration of acetyl-leucine may be initiated when the subject is symptomatic or asymptomatic. In particular, one of the advantages of acetyl-leucine treatment as described herein is that administration of acetyl-leucine may be initiated before the subject shows symptoms of neurodegenerative disease (other than genetic and / or biochemical markers, i.e., the subject is asymptomatic) or before the subject shows one or more symptoms considered to be prominent features of the disease, but at an early stage after the subject is found to have genetic and / or biochemical markers. As described herein, treatment may delay the onset of neurodegenerative disease or one or more symptoms associated with neurodegenerative disease. Treatment may also be continued for a period of time as described herein.

[0073] As described herein, the advantage of acetylleucine treatment according to this disclosure is that acetylleucine may be administered over a long period of time, for example, to delay or even reverse the progression of neurodegenerative disease or the symptoms of one or more neurodegenerative diseases in a subject compared to the typical progression of the disease. 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 may be 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.

[0074] Any combination of dosage form, dose, administration schedule, and treatment duration is envisioned and included in the present invention. In one example, the dose is approximately 4g to 10g per day, administered once, twice, or three times a day for a treatment duration of approximately two months or more. In another example, the dose is more than 4g but not more than 5g per day, administered once, twice, or three times a day for a treatment duration of approximately six months or more. The dosage form may be a solid oral dosage form, particularly a tablet.

[0075] The pharmaceutical composition may be used as a monotherapy (e.g., the use of the active agent alone) to treat neurodegenerative diseases in the subject. Alternatively, the pharmaceutical composition may be used as an adjunct to or in combination with other known therapies to treat neurodegenerative diseases in the subject.

[0076] Neurodegenerative diseases may, though not necessarily, be associated with lysosomal dysfunction (e.g., lysosomal storage defects). According to this disclosure, neurodegenerative diseases not associated with lysosomal dysfunction include, without limitation, Alexander's disease, Alper's disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, HIV-associated dementia, Kennedy's disease, neuroborreliosis, primary lateral sclerosis, Refsum's disease, Schilder's disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, and hereditary motor and sensory neuropathy with proximal muscle predominance. dominance), Wobbly Hedgehog Syndrome (WHS), progressive muscular atrophy (Duchenne-Aran muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorders (HAND), vascular Parkinsonism, lower body Parkinson's syndrome, cerebellar downbeat nystagmus, and cerebellar ataxia.This includes ataxia, where it includes spinocerebellar ataxia (SCA) 4, spinocerebellar ataxia (SCA) 5 (Lincoln's ataxia), spinocerebellar ataxia (SCA) 8, spinocerebellar ataxia (SCA) 10, spinocerebellar ataxia (SCA) 11, spinocerebellar ataxia (SCA) 12, and spinocerebellar ataxia (SCA) 13 (Spinocerebellar Ataxia (SCA) 13), Spinocerebellar Ataxia (SCA) 14, Spinocerebellar Ataxia (SCA) 15 / 16, Spinocerebellar Ataxia (SCA) 18 (Sensory / motor neuropathy with ataxia), Spinocerebellar Ataxia (SCA) 19 / 22, Spinocerebellar Ataxia (SCA) 20, Spinocerebellar Ataxia (SCA) 21 (Spinocerebellar Ataxia (SCA) 21), Spinocerebellar Ataxia (SCA) 23, Spinocerebellar Ataxia (SCA) 25, Spinocerebellar Ataxia (SCA) 26, Spinocerebellar Ataxia (SCA) 27, Spinocerebellar Ataxia (SCA) 29, Spinocerebellar Ataxia (SCA) 30Ataxia (SCA) 30), Spinocerebellar Ataxia (SCA) 31, Spinocerebellar Ataxia (SCA) 32, Spinocerebellar Ataxia (SCA) 35, Spinocerebellar Ataxia (SCA) 36, Episodic Ataxia (EA) 1, Episodic Ataxia (EA) 2, Episodic Ataxia (EA) 3, Episodic Ataxia (EA) 4, Episodic Ataxia (EA) 5 Ataxia (EA) 5), Episodic Ataxia (EA) 6, Episodic Ataxia (EA) 7, Spinocerebellar Ataxia (SCA) 28, Spinocerebellar Ataxia (SCA) 24 (Spinocerebellar Ataxia (SCA) 24) (Autosomal recessive type 4 spinocerebellar ataxia (SCAR4); Spinocerebellar ataxia with saccadic intrusions), Tabes dorsalis, Ataxia with Oculomotor Apraxia Type 1 1) (AOA1), Ataxia with Oculomotor Apraxia Type 2 (AOA2), Ataxia with Oculomotor Apraxia Type 4 (AOA4), Spinocerebellar ataxia autosomal recessive type 10 (SCAR)10) Mitochondrial recessive ataxia syndrome (MIRAS), Myclonic Epilepsy Myopathy Sensory Ataxia (MEMSA), Sensory Ataxic Neuropathy Dysarthria Opthalmoparesis (SANDO), Infantile-onset spinocerebellar ataxia, Hereditary Spastic Paraplegia 7 (HSP SPG7 gene), Mitochondrial myopathy, Encephalopathy, Lactacidosis, Stroke syndrome This includes MELAS syndrome, myoclonic epilepsy with ragged red fibers (MERRF), neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), as well as Kearns-Sayre syndrome (KSS), Fragile X tremor / ataxia syndrome (FXTAS), Arts syndrome, X-linked spinocerebellar ataxia 1, X-linked spinocerebellar ataxia 2, X-linked spinocerebellar ataxia 3, and X-linked spinocerebellar ataxia 4. Ataxia 4) or X-linked spinocerebellar ataxia 55) includes Christianson type X-linked syndrome mental retardation, X-linked sideroblastic anemia, idiopathic late-onset cerebellar ataxia, sporadic adult-onset ataxia of unknown etiology (SAOA), and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In one example, neurodegenerative diseases not associated with lysosomal dysfunction are corticobasal degeneration, SCA28, and AOA4.

[0077] As mentioned above, many neurodegenerative diseases are associated with lysosomal dysfunction, including both neurodegenerative lysosomal storage disorders (LSDs) and many other neurodegenerative diseases that have been suggested to be linked to lysosome deficiencies. See, for example, Boman et al., Journal of Parkinson's Disease, vol.6, no.2, pp.307-315 (May 2016); Makioka et al., Neuroreport, 23(5):270-276 (March 2012); Orr et al., Alzheimer's Research & Therapy, 5:53 (Oct. 2013); Barlow et al., Proc. Nat'l. Acad. Sci. USA, 18;97(2):871-6 (2000).

[0078] In one embodiment, neurodegenerative disease is associated with lysosomal dysfunction (e.g., lysosomal storage defects). According to this disclosure, neurodegenerative diseases associated with lysosomal dysfunction include, but are not limited to, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Canavan disease, frontotemporal lobar degeneration, Huntington's disease, Lewy body dementia, multiple system atrophy (MSA-P / MSA-C), multiple sclerosis, narcolepsy, Parkinson's disease, Smith-Lemli-Opitz syndrome (SLOS) (inborn error of cholesterol synthesis), Tangier disease, Pelizaeus-Merzbacher disease, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, prion diseases including scrapie, and transmissible mink encephalopathy. encephalopathy, chronic wasting disease, bovine spongiform encephalopathy (BSE), feline spongiform encephalopathy, exotic ungulate encephalopathy, kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. Insomnia), progressive supranuclear palsy, spinal muscular atrophy, neurodegenerative LSD, and spinocerebellar ataxia (SCA) 1, spinocerebellar ataxia (SCA) 2, spinocerebellar ataxia (SCA) 3 (Machado-Joseph disease), spinocerebellar ataxia (SCA) 6, spinocerebellar ataxia (SCA) 7, spinocerebellar ataxia (SCA) 17, dentatorubral-pallidoluysian atrophyatrophy), Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), Autosomal recessive cerebellar ataxia type 1 (Recessive Ataxia of Beauce (RAB), SYNE-1 mutant), Autosomal recessive cerebellar ataxia type 2 (Spinocerebellar ataxia autosomal recessive 9, SCAR9), Ataxia with vitamin E deficiency (AVED), Ataxia telangiectasia (Louis Barr disease) This includes spinocerebellar ataxia, including Friedreich's ataxia (FRDA), and ataxia with coenzyme Q10 deficiency. In one example, neurodegenerative diseases associated with lysosomal dysfunction are selected from alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Canavan disease, frontotemporal dementia, Huntington's disease, multiple system atrophy (MSA-P / MSA-C), multiple atrophy, multiple sclerosis, narcolepsy, Parkinson's disease, Smith-Lemle-Oppitz syndrome (SLOS) (congenital cholesterol production disorder), Tangier disease, Pelizaeus-Merzbacher disease, Pick's disease, frontotemporal dementia, frontotemporal dementia with parkinsonism, prion diseases, progressive supranuclear palsy, and spinal muscular atrophy. In one embodiment, the neurodegenerative disease associated with lysosomal dysfunction is selected from ALS, MSA-P, MSA-C, frontotemporal dementia with parkinsonism, progressive supranuclear palsy, SCA 28, SCA 1, and Alzheimer's disease.

[0079] Neurodegenerative LSD is characterized by the accumulation of undigested or partially digested macromolecules resulting in cellular dysfunction and neurodegeneration, which is often progressive and leads to physical and / or mental deterioration. These tend to appear in the first few years of life, and severe progression results in frequent hospitalizations. If left untreated, patients often die in their mid-teens. Adult-onset cases have also been described. According to this disclosure, neurodegenerative LSDs (LSDs) include, but are not limited to, neuronal ceroid lipofuscinosis (types 1-10), Gaucher disease types 2 / 3 (neuropathic), Krabbe disease, multiple sulfatase deficiency, mucolipidosis including mucolipidosis I, mucolipidosis II, and mucolipidosis IV, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C, infant-onset Pompe disease, late-onset Pompe disease, Tay-Sachs disease, Sandhoff disease, Faber disease, galactosialidosis, Fabry disease, Schindler disease, GM1 gangliosidosis, AB variant GM2 gangliosidosis, metachromatic leukodystrophy (MLD), MPS IH, MPS IS, MPS IH-S, MPS II, MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, and MPS This includes mucopolysaccharidosis VII, β-mannosidosis, aspartylglucosamineuria, fucosidosis, Salla disease, infantile free sialic acid storage disease (ISSD), and Danon disease. In one example, neurodegenerative LSD is selected from NPC, NPA, mucolipidosis II, MPS IIIB, aspartylglucosamineuria, mucolipidosis IIIA, MPS VII, Sandhoff disease, Tay-Sachs disease, AB variants of Tay-Sachs disease, and GM1 gangliosidosis. In one example, neurodegenerative disease is not selected from neurodegenerative LSD.

[0080] In one embodiment, the neurodegenerative disease is motor neuron disease. In one embodiment, the motor neuron disease is selected from primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, ALS, Alzheimer's disease, Canavan disease, frontotemporal lobar degeneration, Huntington's disease, multiple sclerosis, narcolepsy, Parkinson's disease, Pelizaeus-Merzbacher disease, and spinal muscular atrophy.

[0081] In one example, the neurodegenerative disease is cerebellar ataxia. In one example, the neurodegenerative disease is Niemann-Pick disease. In one example, the neurodegenerative disease is Niemann-Pick disease type C. In one example, the neurodegenerative disease is Niemann-Pick disease type A. In one example, the neurodegenerative disease is Parkinson's disease. In one example, the neurodegenerative disease is neuropathic Gaucher disease. In one example, the neurodegenerative disease is Tay-Sachs disease. In one example, the neurodegenerative disease is Sandhoff disease. In one example, the neurodegenerative disease is Fabry disease. In one example, the neurodegenerative disease is GM1 gangliosidosis. In one example, the neurodegenerative disease is Louis-Barr syndrome. In one example, the neurodegenerative disease is Alzheimer's disease. In one example, the neurodegenerative disease is Parkinson's disease. In one example, the neurodegenerative disease is multiple system atrophy. In one example, the neurodegenerative disease is multiple system atrophy type C (MSA-C). In one example, the neurodegenerative disease is multiple system atrophy type P (MSA-P). In one example, the neurodegenerative disease is frontotemporal dementia. In one example, the neurodegenerative disease is frontotemporal dementia with Parkinson's disease. In one example, the neurodegenerative disease is lower-body Parkinson's syndrome. In one example, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In one example, the neurodegenerative disease is corticobasal degeneration syndrome. In one example, the neurodegenerative disease is progressive supranuclear palsy. In one example, the neurodegenerative disease is cerebellar nystagmus. In one example, the neurodegenerative disease is SCA28. In one embodiment, the neurodegenerative disease is ataxia telangiectasia. In one embodiment, the neurodegenerative disease is SCA1. In one embodiment, the neurodegenerative disease is AOA4.

[0082] The main symptoms of Parkinson's disease (PD) include muscle rigidity, tremor, and slow movement. Other diseases can also cause these symptoms to spread. These diseases, and PD itself, fall under the collective term Parkinsonism. PD may be called Primary Parkinsonism. Other examples of Parkinsonism include multiple system atrophy; progressive supranuclear palsy; normal pressure hydrocephalus; and vascular or arteriosclerotic parkinsonism. These diseases, which can be classified as Parkinsonism but are not PD, may also be called "Parkinson Plus syndromes." Unlike PD patients, individuals with Parkinson Plus syndromes do not respond to L-dopa. The term "parkinsonism" as used herein may refer to a motor syndrome whose main symptoms are resting tremor, stiffness, slowing of movement, and postural instability. Parkinson's syndrome can be classified into four subtypes depending on its origin: primary or idiopathic; secondary or acquired; hereditary parkinsonism; and parkinson's plus syndrome or multiple system degeneration.

[0083] In one embodiment, Parkinson's disease is Parkinson's Plus syndrome or multiple system degeneration.

[0084] In one example, Parkinson's disease is defined as vascular (arteriosclerotic) Parkinson's syndrome, lower body Parkinson's disease, multiple system atrophy with predominant Parkinsonian symptoms (MSA-P), multiple system atrophy with cerebellar features (MSA-C; sporadic olivopontocerebellar atrophy (OPCA)), Shy-Drager syndrome, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), Lewy body dementia, Pick's disease, or frontotemporal dementia and parkinsonism linked to chromosome 17.

[0085] Niemann-Pick disease is a heterogeneous group of autosomal recessive LSDs (LSDs). Common cellular features include not only hepatosplenomegaly but also abnormal sphingomyelin (SM) accumulation in mononuclear phagocytic cells and parenchymal tissues. Of the three main subgroups of Niemann-Pick disease (A-C), NPC (formerly classified as NPC and NPD, now recognized as a single disease) is classified as a fatal visceral neuronal LSD caused by abnormal intracellular cholesterol transport-inducible accumulation of non-esterified cholesterol in late endosome / lysosomal compartments. Outside the CNS, the cellular characteristics of NPC include abnormal accumulation of non-esterified cholesterol and other lipids (e.g., GSLs) in late endosome / lysosomal compartments. Conversely, in the CNS, there is no net increase in cholesterol (although there is an altered distribution), but there are significantly elevated levels of GSLs. Progressive neurodegeneration is particularly characterized by the continuous degeneration of GABAergic Purkinje neurons in the cerebellum, which parallels the onset and progression of cerebellar ataxia, as well as other aspects of neurological 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 exact mechanistic relationship between these two genes remains unknown, and the functional roles of these proteins remain a mystery. NPC1 encodes a transmembrane protein of the late endosome / lysosome limiting membrane, while NPC2 is a lysosomal soluble cholesterol-binding protein. 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 then leads to defects in calcium influx into the acidic storage compartment, resulting in a significant decrease in calcium release from this compartment. This subsequently prevents late endosome-lysosome fusion, a calcium-dependent process, and causes secondary accumulation of lipids (cholesterol, sphingomyelin, and sphingoglycolipids), which are cargo that pass through the late endocytosis pathway. Other secondary consequences of inhibiting NPC1 function include incomplete endocytosis and the inability to remove autophagous vesicles. The NPC1 / NPC2 cellular pathway has been shown to be targeted by pathogenic mycobacteria to promote their survival in late endosomes.

[0086] The NPC mouse model shares many pathological features with, for example, Alzheimer's disease (AD). Levels of microtubule-associated protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) have been previously reported to be elevated in NPC mice. LC3-II is a marker of autophagosome formation, and elevated levels of LC3-II may reflect impaired clearance of autophagosomes. Autophagosomes are formed but not removed. Autophagy is impaired in AD, and AD brains show elevated levels of LC3-II. Furthermore, amyloid precursor protein (APP) is a precursor molecule whose proteolysis produces β-amyloid (Aβ). Aβ plaques are characteristic of AD brains and have been proposed to be a causative factor in the disease pathology. Amyloid precursor protein C-terminal fragments (APP-CTFs) are intermediates in the proteolytic degradation of APP to Aβ, and they accumulate in the brains of AD patients, and also accumulate progressively in the brains of NPC1 mice.

[0087] Tay-Sachs disease is a fatal genetic disorder of lipid metabolism characterized particularly in CNS tissues due to a deficiency of the A isozyme of β-hexosaminidase. Mutations in the HEXA gene, which encodes the α subunit of β-hexosaminidase, cause the A isozyme deficiency. Tay-Sachs disease is a prototype of a group of disorders similar to GM2 gangliosidosis, characterized by defective GM2 gangliosidosis. GM2 ganglioside (monosialylated ganglioside 2) accumulates in neurons, starting as early as the fetal stage.

[0088] Sandhoff disease results from a deficiency in 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.

[0089] GM1 gangliosidosis is caused by a deficiency of β-galactosidase, which results in the lysosomal accumulation of GM1 ganglioside (monosialylated ganglioside 1).

[0090] Fabry disease is caused by a deficiency of alpha-galactosidase, which results in the accumulation of ceramide trihexoside in lysosomes.

[0091] In one embodiment, the neurodegenerative disease is not cerebellar ataxia. In one embodiment, the neurodegenerative disease is not Niemann-Pick disease. In one embodiment, the neurodegenerative disease is not Niemann-Pick type C disease. In one embodiment, the neurodegenerative disease is not cerebellar ataxia or Niemann-Pick disease (e.g., Niemann-Pick disease type C).

[0092] In one embodiment, acetylleucine, or a pharmaceutically acceptable salt thereof, treats weight loss, gait deterioration, and / or motor dysfunction associated with Niemann-Pick disease (e.g., Niemann-Pick type C or A) or mucolipidosis type II. For example, acetylleucine, or a pharmaceutically acceptable salt thereof, may delay or reverse, eliminate, reduce the severity of, or delay the onset of, weight loss, gait deterioration, and / or motor dysfunction associated with Niemann-Pick disease (e.g., Niemann-Pick type C or A) or mucolipidosis type II. In one embodiment, weight loss, gait deterioration, and / or motor dysfunction are associated with Niemann-Pick type A or mucolipidosis type II.

[0093] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats the gait deterioration, motor impairment, and / or reduced mobility associated with Sandhoff disease. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may slow or reverse the progression of the gait deterioration, motor impairment, and / or reduced mobility associated with Sandhoff disease, eliminate it, reduce its severity, or delay its onset.

[0094] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats (eliminates) the impaired coordination, tremor, impaired motor function, 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 of, eliminate, reduce the severity of, or delay the onset of, the impaired coordination, tremor, impaired motor function, cognitive impairment, and / or gait deterioration associated with Tay-Sachs disease.

[0095] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats speech deterioration (e.g., speech fluency and / or voice modulation), gait deterioration, motor impairment, swallowing impairment, and / or paralysis associated with amyotrophic lateral sclerosis (ALS). For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of speech deterioration (e.g., speech fluency and / or voice modulation), gait deterioration, motor impairment, swallowing impairment, and / or paralysis associated with ALS, or eliminate or reduce their severity, or delay their onset. In another embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats sleep deterioration associated with ALS. For example, acetyl-leucine, or its pharmaceutically acceptable salts, may slow or reverse the progression of sleep quality decline associated with ALS, eliminate it, reduce its severity, or delay its onset.

[0096] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats speech deterioration, gait deterioration, and / or increased tendency to fall associated with multiple system atrophy cerebellar type (MSA-C). For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of speech deterioration, gait deterioration, and / or increased tendency to fall associated with MSA-C, eliminate or reduce their severity, or delay their onset.

[0097] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats gait deterioration, increased tendency to fall, and / or speech deterioration associated with frontotemporal dementia with Parkinson's disease. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of gait deterioration, increased tendency to fall, and / or speech deterioration associated with frontotemporal dementia with Parkinson's disease, eliminate or reduce its severity, or delay its onset.

[0098] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats increased fall tendencies and / or gait deterioration associated with corticobasal degeneration syndrome. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of increased fall tendencies and / or gait deterioration associated with corticobasal degeneration syndrome, eliminate them, reduce their severity, or delay their onset.

[0099] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats gait deterioration associated with progressive supranuclear palsy. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of gait deterioration associated with progressive supranuclear palsy, eliminate it, reduce its severity, or delay its onset.

[0100] In one embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats oscilloscopes, impaired spatial orientation, impaired visual acuity, and / or increased postural sway associated with cerebellar lower eyelid nystagmus. For example, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay or reverse the progression of oscilloscopes, impaired spatial orientation, impaired visual acuity, and / or increased postural sway associated with cerebellar lower eyelid nystagmus, eliminate or reduce its severity, or delay its onset.

[0101] Also provided is a method for treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease in a subject that requires such treatment, the method comprising administering a therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof to the subject.

[0102] The “therapeutic effective dose” of a drug is the amount of the drug required to produce the desired effect when administered to a subject, and may be therapeutic and / or prophylactic for the purposes of this disclosure. The dose 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 disease; the route of administration; and the necessary lifestyle. A physician may determine the necessary route of administration and dose for any particular patient. For example, the daily dose may be about 10 to about 225 mg per kg of body weight, about 10 to about 150 mg per kg of body weight, or about 10 to about 100 mg per kg of body weight.

[0103] A kit for utilizing neurodegenerative diseases in the subject is also disclosed, which comprises means for diagnosing or predicting the disease / disorder, and acetyl-leucine or a pharmaceutically acceptable salt thereof.

[0104] Means for diagnosing or predicting neurodegenerative diseases may include specific binders, probes, primers, primer pairs or combinations thereof, enzymes or antibodies containing antibody fragments, which can detect or aid in the detection of neurodegenerative diseases as defined herein. The kit may include a fluorescent marker, LysoTracker®, which is commercially available from both Invitrogen and Lonza. LysoTracker® may be blue, blue-white, yellow, green, or red.

[0105] The kit also comprises acetyl-leucine or a pharmaceutically acceptable salt thereof, as defined herein. The kit may further comprise a buffer or aqueous solution. The kit may further comprise instructions for using acetyl-leucine or a pharmaceutically acceptable salt thereof in the method of the present invention.

[0106] Further embodiments disclose acetyl-leucine or a pharmaceutically acceptable salt thereof for use in methods that provide neuroprotective effects in subjects with a need (subjects with, suspected of having, or potentially having, neurodegenerative diseases).

[0107] As used herein, “neuroprotective effect” and its cognates mean, without limitation, the prevention, delay, and / or reversal of the progression of neurodegeneration, including the progressive loss of neuronal structure, the progressive loss of neuronal function, and / or the progressive death of nerve cells. Providing neuroprotective effect may result in delaying the onset of neurodegenerative disease or the onset of one or more symptoms of neurodegenerative disease that would otherwise be expected to appear in accordance with typical disease progression, reducing the severity of neurodegenerative disease or reducing or eliminating the severity of one or more pre-existing symptoms associated with neurodegenerative disease, delaying the progression of neurodegenerative disease or the progression of one or more symptoms of neurodegenerative disease over time compared to typical disease progression, and / or reversing the progression of neurodegenerative disease or one or more symptoms of neurodegenerative disease over time. The duration for which neuroprotective effect is provided may coincide with the duration of treatment as described herein. The treatment may provide neuroprotective effects for a period of time, for example, 7 days or more, 2 weeks or more, 3 weeks or more, 1 month or more, 6 weeks or more, 7 weeks or more, or 2 months or more. The treatment may provide neuroprotective effects for a period of time, for example, 3 months or more, 4 months or more, 5 months or more, or 6 months or more. It may also provide neuroprotective effects for a period of time, for example, 1 year or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, or 10 years or more. The treatment may provide neuroprotective effects for the lifespan of the patient.

[0108] In another embodiment, a method for providing neuroprotection in subjects in need (e.g., subjects with, suspected of having, or at risk of having, a neurodegenerative disease) comprises administering a therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt to the subject.

[0109] Kits for providing neuroprotection in subjects who have, are suspected of having, or are at risk of having, a neurodegenerative disease are also disclosed, the kits comprising means for diagnosing or predicting the disease / disorder, and acetyl-leucine or a pharmacologically acceptable salt thereof.

[0110] This disclosure further includes the use of acetyl-leucine or a pharmaceutically acceptable salt thereof as a neuroprotective agent in subjects where there is a need for it (for example, subjects having, suspected of having, or potentially having a neurodegenerative disease).

[0111] All features described herein (including the attached claims, abstract and drawings), and / or all steps of any method disclosed herein may be combined with any aspect of the foregoing in any combination, except for at least some combinations in which such features and / or steps are mutually exclusive.

[0112] Experimental example The present invention will be further described in the following experimental examples, which demonstrate the usefulness of acetylleucine in treating neurodegenerative diseases in subjects and in providing neuroprotective effects in said subjects.

[0113] Experimental Example 1 In vivo mouse studies - methods Mouse Model This study uses a genuine mouse model of an NPC, Npc1 - / - (BALB / cNctr-Npc1 m1N / J) Mice were used, but this was ineffective against the NPC1 protein and exhibited all the characteristics of the clinical disease (Loftus, 1997).

[0114] This mutant strain occurs spontaneously, has a lifespan in the range of 10 - 14 weeks, and therefore has a more acute disease (illness) course than most patients. This mutant mouse has been successfully utilized not only to determine the ontogeny of the disease and the underlying pathogenesis, but also to evaluate experimental treatment methods. Analyses using these mice have been conducted at the whole animal, cell, and molecular levels (Baudry, 2003; Smith, 2009; Cologna, 2014; Cologna, 2012). It is the most intensively studied animal model of NPC.

[0115] Before about 4 - 5 weeks of age, Npc1 - / - mice did not have distinguishable behavioral signs of disease that would distinguish them from wild - type littermates. The first signs of behavioral deficits such as tremors and ataxic gait appeared by 5 - 6 weeks, the impairment of motor coordination became more evident by 7 - 8 weeks, ataxia progressed by 9 - 10 weeks, and as feeding and drinking became difficult, there was an increasing loss of body weight and poor coat condition (humane end point is applied) (Smith, 2009).

[0116] Wild - type (Npc1 + / + ) littermates were used as controls.

[0117] 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 of acetyl - DL - leucine provided mixed in mouse chow. As controls, separate groups of Npc1 - / - and Npc1 + / + mice were left untreated.

[0118] Coat Condition Npc1 with and without acetyl - DL - leucine treatment - / -The coat condition of mice was compared by simple observations of 9-week-old mice.

[0119] Weight data The animals' body weight was measured twice a week. Body weight was averaged across all mice in each group, and then compared.

[0120] Gait analysis The CatWalk® 15.0 system was used according to the manufacturer's instructions (Noldus, Nottingham, UK) to analyze the gait of 8-week-old mice. Five experiments were recorded for each animal.

[0121] The measured CatWalk (registered trademark) parameters were as follows: 1. Stand Mean: The average duration (in seconds) of the paw in contact with the glass plate. 2. Step cycle: The duration (s) between two consecutive contacts of the same limb (paw); 3. Duty Cycle: The percentage of time spent in contact with the plate (paws) compared to the time taken to complete the step cycle; 4. Step Sequence (AB): Percentage of time spent walking in an alternating LF-RH-RF-LH pattern (LF: left front; RH: right rear; RF: right front; LH: left rear); 5. Cadence: Steps per second in a 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).

[0122] Motor function analysis Motor function analysis was performed on 8-week-old 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 a bedding area and analyzed for 5 minutes. Rears were counted manually.

[0123] The measured motor function parameters were as follows: 1. Centre Rearing: Rearing of the mouse using its hind legs without support; 2. Rearing: Rearing of the mouse using its hind legs, with and without cage wall support; 3. Activity: Regular movement of an animal, including walking; 4. Front to Back (FR) count: The animal's movement from the front to the back of the cage. 5. Active Time: The duration (s / min) of activity, regardless of movement. 6. Mobile Time: The duration of mobility (seconds / minute); 7. Rearing Time: The duration of any rearing.

[0124] result Court Condition Figure 1B shows an untreated Npc1. - / - This shows littermates of the same age. Npc1 - / - The mice had difficulty eating and drinking, and their coat condition was observed to be poor at 9 weeks of age (see Figure 1B).

[0125] In stark contrast, Figure 1A shows Npc1 treated with acetyl-DL-leucine from weaning. - / - A mouse is shown. Npc1 treated with acetyl-DL-leucine. - / - The mouse is wild type (Npc1 + / + It had a smooth and glossy coat, reminiscent of a littermate (see Figure 1A).

[0126] Weight data As can be seen in Figure 2A, the wild type (Npc1 + / + The mice steadily gained weight during the study period (i.e., from 3 weeks to 10 weeks of age). Furthermore, Figure 2A shows the weight gain at each point in time (Npc1 - / - Untreated, n=1; Npc1 - / - Acetyl-DL-leucine 0.1 g / kg, n=3; Npc1 + / + Untreated, n=3; Npc1 + / + The average body weight per group of mice is shown, with acetyl-DL-leucine at 0.1 g / kg (n=2).

[0127] Treatment with acetyl-DL-leucine did not have a significant effect on this weight gain.

[0128] Npc1 - / - The mouse initially uses Npc1 + / + Weight increased to almost the same extent as the control group. However, Npc1 - / - The mice began to lose weight from 6 weeks of age. By the end of the experiment (10 weeks of age), the mice's weight was as low as it was at just 4 weeks of age.

[0129] Treatment with acetyl-DL-leucine delayed these weight loss symptoms by two weeks compared to the untreated group.

[0130] Npc1 with and without acetyl-DL-leucine treatment - / - Figure 2B shows a comparison of the weight changes in mice. In particular, Figure 2B shows Npc1 - / - This figure shows the percentage change in body weight per group of mice at each time point, but only for mice. The beneficial effect of acetyl-DL-leucine treatment in slowing weight loss is evident from this figure.

[0131] Gait analysis The results of the gait analysis are shown in Figure 3. Diagonal support, cadence, and step sequence data are shown in Figures 3A to 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. Untreated Npc1 + / + For n=3, Npc1 + / + For treatment, n=2, Npc1 - / - For untreated, n=1 (therefore, no statistical analysis is performed), Npc1 - / - For the treatment (treatment), n=3.

[0132] The first bar in each graph represents the wild type (Npc1 + / + ) Shows the walking characteristics of mice.

[0133] The second bar in each graph represents the wild-type (Npc1) treated with acetyl-DL-leucine. + / +The gait characteristics of the mice are shown. There were no significant differences in gait characteristics between these mice and their untreated littermates.

[0134] The third bar in each graph represents Npc1 - / - This shows the walking characteristics of the mouse. Generally speaking, this mouse is Npc1 + / + Compared to mice, the mice exhibited impaired gait. Mice spent very short periods of time, if any, on diagonal support (Figure 3A) or step sequences (Figure 3C), and hind paw function in the stand mean (Figure 3F) and duty cycle (Figure 3G) were also dramatically impaired.

[0135] The fourth bar in each graph represents Npc1 treated with acetyl-DL-leucine. - / - The gait characteristics of the mice are shown. These mice showed significantly improved gait compared to their untreated littermates. In fact, they were Npc1 + / + It exhibited walking characteristics similar to those of mice.

[0136] Motor function analysis Analysis at 8 weeks of age was performed using Npc1. - / - Mouse and wild type (Npc1 + / + ) It was revealed that there was no difference in motor function characteristics between the mice and the animals (data not shown).

[0137] However, by 9 weeks of age, defects in motor coordination became apparent.

[0138] The results of the motor function analysis at 9 weeks of age are shown in Figure 4. Centre rearing, activity, rearing, and front-to-back (FR) counts are shown in Figures 4A to 4D, respectively. Active time, mobile time, rearing time, and total manual rearing counts are shown in Figures 4E to 4H, respectively. Data are expressed as mean ± SEM. Npc1 + / + n=3 for untreated, Npc1 + / + For treatment, n=2, Npc1 - / - For untreated, n=1 (therefore, no statistical analysis is performed), Npc1 - / - For "treated," n=3.

[0139] The first bar in each graph represents the wild type (Npc1 + / + ) This shows the motor function characteristics of mice.

[0140] The second bar in each graph represents the wild-type (Npc1) treated with acetyl-DL-leucine. + / + This shows the motor function characteristics of the mice. There were no significant differences in motor function characteristics between these mice and their untreated littermates.

[0141] The third bar in each graph represents Npc1 - / - This shows the motor function characteristics of the mouse. Generally speaking, this mouse is Npc1 + / + Compared to mice, the mice exhibited poor motor function. Mice spent very little time rearing (panel H), especially unsupported rearing (panel H), particularly with their hind legs (panel A).

[0142] The fourth bar in each graph represents Npc1 treated with acetyl-DL-leucine. - / -This shows the motor function characteristics of the mice. These mice showed significantly improved motor function compared to their untreated littermates. In fact, they were Npc1 + / + It exhibited motor function characteristics similar to those of mice.

[0143] lifespan Npc1 - / - Treatment of mice with acetyl-DL-leucine (0.1 g / kg from 3 weeks of age) was also observed to be associated with a statistically significant increase in lifespan (Figure 5). This data further demonstrates the effect of acetyl-leucine in delaying the onset of disease.

[0144] conclusion Npc1 - / - When mice exhibited distinguishable signs of disease (disorder) that differentiated them from wild-type littermates at 5-6 weeks of age, Npc1 was treated with acetyl-DL-leucine from weaning. - / - The littermates did not show such signs until more than two weeks later. Npc1 by acetyl-DL-leucine - / - The treatment in mice delayed the onset and progression of NPC symptoms and demonstrated evidence of neuroprotective effects.

[0145] Since acetyl-DL-leucine produced a general neuroprotective effect, it is reasonable to expect that the results observed in NPCs would also be observed in other neurodegenerative disorders, as well as neurodegenerative disorders associated with defects in lysosome storage.

[0146] Experimental Example 2 method Fibroblast cell lines derived from NPC patients were treated with N-acetyl-DL-leucine (1 mM) for 3 days, and the relative lysosome volume was quantified via LysoTracker, a fluorescent dye that accumulates in acidic organelles. Increased LysoTracker fluorescence indicates an increase in lysosome size and / or number, which is a prominent feature of NPC cells.

[0147] Furthermore, fibroblasts derived from patients with Niemann-Pick A (NPA), mucolipidosis type II (MLII), mucopolysaccharidosis type IIIB (MPS IIIB), aspartylglucosamineuria, mucolipidosis type IIIA (MLIIIA), and mucopolysaccharidosis type VII (MPS VII) were treated with acetyl-DL-leucine (1 mM) for 6 days, and lysosomal volume was quantified by LysoTracker.

[0148] 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 a decrease in lysosome volume over time (Figure 6A). These findings were replicated in fibroblasts from additional NPC patients with variable clinical severity treated with 1 mM N-acetyl-DL-leucine for 72 hours (Figure 6B).

[0149] Fibroblasts derived from patients with NPA, MLII, MPS IIIB, aspartylglucosamiuria, MLIIIA, and MPS VII were observed to have elevated LysoTracker fluorescence levels compared to age-matched wild-type controls (Figures 6C–6H). This indicates expanded lysosomal development resulting from lipid accumulation, compared to fibroblasts from healthy individuals. Treatment with acetyl-leucine was associated with a statistically significant decrease in LysoTracker fluorescence towards control levels in MPS IIIB fibroblasts and MLII and MPS IIIB fibroblasts relative to both NPA and MLII and untreated NPA, respectively (Figures 6C-6E), and was associated with a tendency to decrease LysoTracker fluorescence towards control levels in MPS VII fibroblasts and MLIIIA and MPS VII fibroblasts relative to aspartylglucosamineuria, MLIIIA and untreated aspartylglucosamineuria, respectively (Figures 6F-6H). The decrease in LysoTracker fluorescence indicated a decrease in lysosomal volume (Figures 6C-6H and 6D). The data presented in Figures 6A to 6D represent lysosome volume as a magnification change relative to untreated wild-type fibroblasts, showing the results 6 days after treatment with 1 mM acetyl-leucine for each cell line. Asterisks (* / ****) indicate the p-value (<0.05 / 0.001) relative to untreated diseased fibroblasts.

[0150] conclusion N-acetyl-DL-leucine treatment was associated with regulating disrupted lysosomal storage by reducing lysosomal volume; thus, acetyl-leucine directly modified the phenotype of these lysosomal storage disorders. These diseases represent different classes of LSDs, and these results further support the usefulness of acetyl-leucine's effects on a wide range of lysosomal storage disorders.

[0151] Experimental Example 3 Sandhoff disease is a disorder that may result from autosomal recessive inheritance of a mutation in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. As a result, GM2 gangliosides cannot be degraded and accumulate in lysosomes within cells of the peripheral and central nervous system (CNS).

[0152] This study, as described by Jeyakumar et al., uses a mouse model of Sandhoff disease, Hexb - / - This study used mice (Jeyakumar et al. (1999) Proc. Natl. Acad. Sci. USA 96:6388-6393).

[0153] Wild type (Hexb + / + The mouse was used as a control.

[0154] lifespan Treatment with acetyl-DL-leucine was associated with a statistically significant increase in the lifespan of Sandhoff disease 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 compared to untreated Sandhoff disease mice. Data are the mean of n=6 mice per group. Without treatment, the median survival time of Sandhoff disease mice was 112 days. Treatment with acetyl-leucine (0.1 g / kg body weight from 3 weeks of age) increased the median lifespan to 120 days.

[0155] motor function Treatment of Sandhoff disease mice with acetyl-leucine resulted in improvements in motor function, as demonstrated by the Bar Crossing and Step Cycle studies.

[0156] Bar Crossing Test The bar crossing test is a method for evaluating motor function in mice, in which the mouse is placed suspended from the middle of a horizontal bar by its forelimbs. A wild-type mouse with normal motor function can coordinate its hindlimbs, thereby moving to one of the platforms at either end of the bar, and thus complete the test.

[0157] Untreated Sandhoff disease mice can complete the test until approximately 11 weeks of age. Beyond this point, motor function and hindlimb mobility / coordination deteriorate to the point where the mouse will no longer be able to complete the test and will fall from the bar onto the padded surface below.

[0158] Treatment with acetyl-DL-leucine (0.1 g / kg body weight from 3 weeks of age) in a Sandhoff disease mouse model was associated with improved motor function and hindlimb mobility / coordination, as assessed by the bar crossing test (Figure 7B). In Figure 7B, acetyl-leucine treatment at 0.1 g / kg body weight was provided from 3 weeks of age. Acetyl-leucine-treated Sandhoff disease mice retained the ability to complete the test (including end tests) up to 13 weeks of age. The data shown are averages from 6 mice per group. Treated Sandhoff disease mice retained the ability to complete the test (including end tests) up to 13 weeks of age.

[0159] Step Cycle The step cycle is the length of time between limb (foot) movements, from the moment one limb leaves the ground until the next time it leaves the ground.

[0160] Step-cycle times were evaluated at 12 weeks of age in untreated and acetyl-leucine-treated Sandhoff disease model mice. Acetyl-leucine treatment consisted of 0.1 g / kg body weight of acetyl-leucine starting at 3 weeks of age.

[0161] Treatment with acetylleucine in a Sandhoff disease mouse model was associated with significantly faster pre-step cycle times (p<0.05 vs. untreated SH mice), significantly faster posterior step cycle times (p<0.01 vs. untreated SH mice), and significantly faster mean step cycle times (p<0.001 vs. untreated SH mice) (Figure 7C). In Figure 7C, acetylleucine treatment at 0.1 g / kg body weight was provided from 3 weeks of age. Pre-step cycle refers to the forelimbs (feet) of the mouse, posterior step cycle refers to the hindlimbs (feet) of the mouse, and mean step cycle takes into account all limbs (feet) of the mouse. Asterisks (* / ** / ***) indicate p-values ​​<0.05 / 0.01 / 0.001 compared to untreated Sandhoff disease mice. The data shown are mean ± standard deviation.

[0162] Thus, acetyl-leucine treatment was associated with faster step cycles in the Sandhoff disease mouse model, which may indicate an improvement in motor function.

[0163] conclusion These studies demonstrate that acetyl-leucine treatment in a mouse model of Sandhoff disease may produce not only a significantly increased lifespan but also improvements in motor function, as assessed by two independent experiments.

[0164] Example 4 GM2 gangliosidosis is a group of lysosomal storage disorders resulting from defects in β-hexosaminidase activity. This group includes Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease.

[0165] Fibroblasts derived from GM2 patients (Tay-Sachs disease, Sandhoff disease, and AB variants of Tay-Sachs disease) and healthy controls were treated with acetyl-DL-leucine (1 mM over 6 days) before extraction and quantification of sphingoglycolipid (GSL) levels by high-performance liquid chromatography (HPLC).

[0166] In the absence of treatment, fibroblasts derived from all three types of GM2 gangliosidosis showed elevated GSL levels compared to untreated wild-type controls. In all three cases, treatment with acetyl-DL-leucine (1 mM over 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 variants of Tay-Sachs disease, there was a tendency toward decreased GSL levels associated with treatment. The data presented in Figures 8A-8C are shown as a multiplier change relative to the level in untreated wild-type fibroblasts, and also as the results of treatment for each cell line in GSL levels adjusted for protein content.

[0167] Example 5 patient 1 The patient in this case study was a 28-year-old male who was genetically diagnosed with Tay-Sachs disease and presented with motor dysarthria, tremor, ataxia of the stance and gait, paraplegia, and muscle atrophy. Specifically, the patient was unable to stand or walk, although he could take a step with strong support. He exhibited distinctly different postural sway, oculomotor dysfunction, dysphagia, and dysarthria, as well as mild cognitive impairment. The first symptoms were observed at age 16.

[0168] Prior to the initiation of treatment, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5 / 40. Furthermore, the results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking test (8MW): 21.6 seconds (8-meter Walking Test) 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)

[0169] For later comparison, videos of the patients were also recorded.

[0170] The day after this test, the patient began treatment with acetyl-leucine at a dose of 3g per day for the first week, and then at a dose of 5g per day from the second week onward.

[0171] At one and four months, the patient was re-examined while continuing treatment. At one month, the patient had improved fine motor skills and reduced hand tremors, for example, during eating or drinking. Walking remained largely unchanged. At four months, the patient was stable with slightly improved cognitive function but showed deterioration in stance, walking, and fine motor skills. The patient's SARA score and the results of the patient's SCAFI analysis are shown below compared to baseline.

[0172] [Table 1]

[0173] Overall, patients showed improvement in symptoms after acetyl-leucine treatment.

[0174] patient 2 The patient in this case study was a 32-year-old woman who was genetically diagnosed with Tay-Sachs disease and presented with ataxia of stance and gait, fine motor impairment, lower limb paralysis, and muscle atrophy. In particular, she was unable to walk without support, and the patient suffered from dysphagia and dysarthria, oculomotor dysfunction, and mild cognitive impairment. The first symptoms were observed at age 7.

[0175] Prior to the initiation of treatment, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 10.5 / 40. Furthermore, the results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking 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)

[0176] For later comparison, we also recorded videos of the patients.

[0177] On the day of the examination, the patient 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.

[0178] One month later, the patient was re-examined while continuing treatment and showed increased speech, improved postural stability, and enhanced cognitive function. Stance and walking were possible without support. The patient's SARA score and SCAFI analysis results are shown below compared to baseline.

[0179] [Table 2]

[0180] patient 3 The patient in this case study was an 8-year-old male who was genetically diagnosed with Tay-Sachs disease and had epileptic seizures (tonic-clonic, approximately 10 seconds, self-limited) almost daily before falling asleep, oculomotor dysfunction, dysarthria, and distinctly different problems with cognitive function and concentration (neurological examination was not possible). He was unable to stand or walk on his own and was severely limited in his daily activities (unable to eat, wash, or dress himself). The first symptoms were observed at 9 months of age.

[0181] Prior to initiating treatment, the patient's examination revealed 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 score of 50, and an 8MWT score of 18.1 (only if strong support was available).

[0182] The patient started treatment with acetyl-leucine at a dose of 1.5 g per day during the first week, and then received a dose of 3 g per day from the second week onward.

[0183] One month later, the patient was re-examined while continuing treatment and showed improved fine motor skills (able to grasp small objects), increased motivation (more frequent attempts to walk independently), improved postural stability, gait and stance, and was able to speak a word. The patient's SARA, mRDS, EQ-5D-5L visual scales, and 8MWT scores are shown below compared to baseline.

[0184] [Table 3]

[0185] Example 6 The patient in this case study was a 13-year-old male who was genetically diagnosed with GM1 gangliosidosis and was unable to stand or walk on his own, with very limited daily activities (unable to eat, wash, or dress himself). He also had oculomotor dysfunction, dysarthria, and significant problems with cognitive function and concentration (neurological examination was not possible). The first symptoms were observed at age 2.

[0186] Prior to initiating treatment, the patient's examination revealed a 35 / 40 Scale for Assessment and Rating of Ataxia (SARA) score, a 15 mRDS score, and a 50 EQ-5D-5L visual scale score.

[0187] The patient started treatment with acetyl-leucine at a dose of 1.5 g per day during the first week, and then received a dose of 3 g per day from the second week onward.

[0188] One month later, the patient was re-examined while continuing treatment and showed a stable overall condition, increased (more fluid) gait, and stable stance in a natural position. The patient's SARA, mRDS, and EQ-5D-5L visual scale scores were compared to baseline and are shown below.

[0189] [Table 4]

[0190] Experimental Example 7 patient 1 The patient in this case study was a 73-year-old man who had previously been diagnosed with amyotrophic lateral sclerosis (ALS).

[0191] The patient's symptoms were characterized by progressive dysarthria (nasal voice and slurred speech) and right dorsiflexor muscle weakness resulting from foot drop over the past three years.

[0192] Clinically, the patient presented with bulbar speech, paralysis of 3 / 5 of the dorsiflexor muscles of the right foot and large toe lifts, generalized exaggerated reflexes, and increased spastic tone in the right lower limb. EMG showed spontaneous activity, and cMRT showed no indication of any pathological changes.

[0193] The patient began taking riluzole around the time of their ALS diagnosis. However, their clinical symptoms did not change.

[0194] Next, the patient began treatment with acetyl-DL-leucine at a dose of 3 grams per day during the first week, and then at a dose of 5 grams per day from the second week onward. The results were recorded on video.

[0195] Fifteen days after treatment, a health checkup was conducted, and the patient reported a significant improvement in speech. The patient was able to speak more fluently and better control their voice compared to before medication (recorded on video).

[0196] Twenty days later, a further examination was conducted, during which the patient reported further improvement in speech. Furthermore, the patient reported improvement in gait. Right foot dorsiflexor paralysis, and consequently foot drop, dramatically improved and became clinically almost undetectable. Additionally, the patient reported improved sleep, falling asleep earlier, sleeping longer, and feeling noticeably more rested in the mornings.

[0197] The patient continued treatment for approximately 30 more days. A health checkup was performed about 7 days after the patient discontinued treatment, but the patient did not report any further subjective improvement in either right dorsiflexor muscle paralysis or speech. Sleep also worsened. One to two weeks after acetyl-leucine treatment, the patient reported a worsening of speech. At that point, the patient resumed treatment and reported stable symptoms about two months later. A slight worsening of speech was observed compared to when acetyl-leucine treatment was first started.

[0198] The patient did not see any improvement in speech, so they requested that the medication be discontinued. Approximately 2-3 weeks later, the patient again reported a worsening of speech after discontinuing acetyl-DL-leucine treatment. The patient resumed treatment and reported improved symptoms, particularly in speech.

[0199] Overall, patients showed improvement in symptoms following acetyl-leucine therapy.

[0200] patient 2 The patient in this case study was a 74-year-old man who had previously been diagnosed with ALS.

[0201] The patient's symptoms were characterized by progressive dysarthria (nasal voice and slurred speech), weakness during walking for more than one year, and paralysis of the left upper limb for approximately four months. EMG showed generalized polyphasic activity and chronic neurogenic impairment in the bulbar, cervical, and lumbar regions.

[0202] Clinical examination of the patient revealed severe dysarthria, hypomotility, 2 / 5 to 3 / 5 paralysis of the left arm with impaired fine motor skills, general exaggerated reflexes, and fasciculations. Riluzole medication had been started one month prior.

[0203] The patient started treatment with acetyl-DL-leucine at a dose of 3 g per day for the first week, and then increased to 5 g per day from the second week onward.

[0204] Approximately two months later, the patient was re-examined and reported a progressive deterioration in motor function of his left hand, but also a discontinuous improvement in his gait. In addition, his swallowing function remained stable.

[0205] patient 3 The patient in this case study was a 66-year-old man who had previously been diagnosed with ALS.

[0206] The patient's symptoms were characterized by progressive weakness and atrophy of the proximal muscles of both upper limbs, slight impairment of fine motor skills, and general fasciculations and spasms. EMG showed pathological spontaneous activity and chronic neurological changes, while MRT of the brain and cervical column showed no pathological changes. Riluzole was initiated.

[0207] Approximately two months later, clinical examinations showed 3 / 5 to 4 / 5 paralysis of both the shoulder and proximal arm, decreased fine motor skills, general fasciculations, and normal reflexes. The patient was treated with acetyl-DL-leucine, starting at a dose of 3 g per day for the first week, and then increased to 5 g per day from the second week onward.

[0208] One month later, the patient reported no improvement in upper limb muscle strength and no improvement in symptoms. Medication with acetyl-DL-leucine was discontinued, and the patient was asked to report any worsening of symptoms.

[0209] patient 4 The patient in this symptom study was a 66-year-old male diagnosed with ALS. His symptoms were characterized by progressive weakness and atrophy of the proximal upper limbs, slight impairment of fine motor skills, and general fasciculations and spasms. Electromyography showed pathological spontaneous activity and chronic neurological changes. MRI of the brain and cervical column showed no signs of pathology. Treatment with riluzole was initiated.

[0210] Clinical examination revealed 3 / 5 to 4 / 5 paralysis of both the shoulder and proximal arm, impaired fine motor skills, general fasciculations, normal reflexes, and an ALS-FRS score of 44 / 48.

[0211] The patient began treatment with acetyl-DL-leucine at a dose of 3 g per day for the first week, and then increased to 5 g per day from the second week onward.

[0212] Approximately one month later, the patient reported subjective improvement in dysphagia and a decrease in excessive salivation. His relatives reported an improved and more lively facial expression. Limb weakness remained unchanged. Treatment was discontinued, and 10 days later, the patient reported a worsening of symptoms, particularly subjective worsening of dysphagia and excessive salivation. The patient resumed continuous treatment.

[0213] The patient was re-evaluated approximately 8 weeks later, and their symptoms remained stable. The patient's ALS-FRS score was 43 / 48. Compared to the symptoms at the time of diagnosis, there was only slight progression in gait and upper limb weakness.

[0214] Experimental Example 8 Acetyl-leucine therapy has been shown to bring improvement in three patients diagnosed with multiple system atrophy-C.

[0215] patient 1 Patient 1 in this case study was a woman in her late 50s who had presented with progressive ataxia with speech and gait disturbances over the past three years.

[0216] Clinical examination of the patient revealed central cerebellar oculomotor signs, moderate dysarthria, mild limb ataxia, and moderate ataxia of stance and gait. Furthermore, the patient's MRI showed atrophy of the cerebellum and brainstem, particularly the pons and midbrain. Therefore, the patient was diagnosed with MSA-C.

[0217] The patient started treatment with acetyl-DL-leucine at a dose of 5g per day (2g upon waking, 1.5g before lunch, and 1.5g before dinner).

[0218] One week after treatment, the patient had already shown significant improvement in speech.

[0219] patient 2 The patient in this case study was a 77-year-old male diagnosed with MSA-C.

[0220] The patient's symptoms were characterized by the progressive difficulty of walking and an insecure gait with a tendency to fall (the patient fell about 10 times a month). The patient showed dizziness, hypokinetic-rigid syndrome, impulsive eye movements, dysmetria in the coordination test, and autonomic dysfunction, such as urinary incontinence, orthostatic hypotension, and erectile dysfunction, over a 4-year follow-up period.

[0221] Before treatment was initiated, the patient's symptoms remained unchanged for at least a 3-month period.

[0222] The patient started treatment with a dose of 3 grams of acetyl-DL-leucine per day for the first week and subsequently increased the dose to 5 grams per day.

[0223] After 3 weeks of treatment, further examinations were conducted. The patient and his wife reported a significant improvement in walking, stating that the patient walked more steadily and the falls had completely disappeared. Furthermore, the dizziness experienced by the patient was substantially improved.

[0224] The patient was instructed to discontinue the medication, and 1 week later, the patient reported a deterioration in walking and dizziness. The patient reported feeling a more unstable gait with a strong tendency to fall.

[0225] Subsequently, the patient was instructed to resume the medication, which he continued for an additional 40 days and then stopped again. In a clinical examination 7 days after discontinuation of the administration, the patient confirmed a progressive decline in walking and dizziness 2 days after stopping the treatment, and a very strong tendency to fall 5 days after stopping the treatment. Thereafter, the patient returned to continuous treatment.

[0226] patient 3 The patient in this case study was a 76-year-old man diagnosed with MSA-C with poor symptoms.

[0227] The patient's symptoms were characterized not only by dizziness but also by progressive difficulty walking and gait (without falling).

[0228] Clinically, the patient exhibited saccadic eye movements and dysmetria on coordination tests. cMRI showed midbrain atrophy, and FDG-PET of the brain showed decreased metabolism in the striatum and cerebellum. Posturography indicated a high tendency to fall.

[0229] Prior to the initiation of treatment, the patient's clinical symptoms remained unchanged for at least one year.

[0230] Gait analysis was performed, revealing ataxic gait, decreased speed and increased track width compared to the normal range, and gait variability. The patient was then treated with acetyl-DL-leucine at a dose of 3 grams per day during the first week, followed by a dose of 5 grams per day from the second week onward.

[0231] After one month of treatment, further examinations were conducted. Gait analysis showed improvements in walking speed, as well as a reduction in track width and gait sway.

[0232] [Table 5]

[0233] The patient was instructed to discontinue the medication, but approximately 2-3 weeks after discontinuing it, he reported a progressive worsening of his walking ability and dizziness.

[0234] Subsequently, the patient returned to continuous treatment, and symptoms improved again. Treatment was discontinued again, and the patient was evaluated three weeks later. The patient reported a worsening of symptoms, particularly dizziness. Gait analysis showed an increased gait length comparable to the pre-treatment state:

[0235] [Table 6]

[0236] Experimental Example 9 The patient in this case study was a 59-year-old male with progressive personality changes characterized by apathy, inactivity, and apathy. In addition, the patient presented with left-sided hypokinesia syndrome, primarily characterized by impaired fine motor skills and reduced resonance in the left arm. Furthermore, the patient exhibited generalized bradykinesia and gait disturbance, accompanied by small steps and 2-3 falls per month. The patient also presented with slurred speech and cognitive impairment, with reduced psychomotor function and decreased fluency of meaningful words.

[0237] The patient was diagnosed with frontotemporal dementia with Parkinson's disease, and Datscan revealed a decrease in dopamine receptors supporting the diagnosis. Brain FDG-PET showed primarily frontal reduced metabolism.

[0238] The patient showed little improvement during treatment with L-dopa and ropinirol.

[0239] The patient started treatment with acetyl-DL-leucine at a dose of 3 grams per day for one week, and then at a dose of 5 grams per day for four weeks.

[0240] After approximately one month of acetyl-leucine treatment, the medication was discontinued, and the patient was re-examined 13 days later.

[0241] The patient, his wife, and his daughter reported a significant improvement in his gait during acetyl-leucine treatment, and furthermore, that the patient's falls had ceased. The patient also showed improvement in speech, which was less slurred, more understandable, and subjectively much better controlled. After discontinuing treatment, his symptoms worsened.

[0242] Experimental Example 10 The patient in this case study was a 75-year-old man with progressive unstable gait disorder and dizziness that caused backward falls. In addition, this patient presented with mainly left-sided hypokinetic rigid syndrome accompanied by apraxia and alien-limb phenomenon.

[0243] The patient was diagnosed with corticobasal syndrome. Datscan revealed a decrease in dopamine receptors, and MRI showed an atrophic motor cortex in the right hemisphere supporting the diagnosis.

[0244] The patient did not show improvement during treatment with L-Dopa.

[0245] The patient started treatment with acetyl-DL-leucine, administered at a dose of 3 g per day for the first week and then 5 g per day thereafter. Gait analysis was performed before starting the treatment.

[0246] After 20 days of acetyl-leucine treatment, the patient was re-examined. Improvement in dizziness symptoms and a significant decrease in the frequency of falls were observed.

[0247]

Table 7

[0248] For example, there was objective improvement in gait analysis parameters such as speed, maximum speed, cadence, and reduced double stance (Table 2 and Figure 9).

[0249] Eight weeks after acetyl-leucine treatment, the medication was discontinued, and the patient was re-examined 6 days later.

[0250] The patient reported an increase in dizziness symptoms (a feeling of being drunk) 2 days after the interruption of treatment.

[0251] Thereafter, the patient returned to continuous treatment.

[0252] Experimental Example 11 patient 1 The patient in this case study was a 76-year-old woman with dizziness that primarily occurred while walking. No falls were reported. The patient also presented with gait disturbances involving small steps, and generalized bradykinesia and vertical gaze palsy with impaired fine motor skills.

[0253] The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a decrease in dopamine receptors, and FDG-PET of the brain showed decreased metabolism, primarily in the frontal bone, confirming the diagnosis.

[0254] The patient showed little improvement during treatment with L-dopa.

[0255] The patient was treated with acetyl-DL-leucine at a dose of 3 g per day for one week, followed by a dose of 5 g per day for four weeks. After 27 days of acetyl-leucine treatment, the medication was discontinued, and the patient was re-examined 60 days later.

[0256] The patient reported a significant reduction in dizziness and a slight improvement in gait under treatment with acetyl-leucine. After discontinuation of treatment, symptoms worsened.

[0257] The patient was re-examined approximately two months later and reported stable symptoms of underlying progressive supranuclear palsy. The PSPRS score remained stable, and the reduction in dizziness was still significant.

[0258] patient 2 The patient in this case study was a 66-year-old woman with vertical gaze palsy accompanied by symmetrical dyskin-rigidity syndrome, gait disturbance with unstable and small steps (strong tendency towards stepping), and impaired fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a decrease in dopamine receptors, and FDG-PET of the brain showed primarily frontal reduced metabolism, supporting the diagnosis. There was no levodopa response.

[0259] The patient initiated treatment with acetyl-DL-leucine, receiving a dose of 3 g per day for the first week, followed by 5 g per day thereafter. A gait analysis was performed before initiating treatment. After 17 days of treatment, medication was discontinued, and the patient was re-examined 4 days later. The patient did not report any significant improvement in gait or hypokinetic rigidity syndrome.

[0260] [Table 8]

[0261] The patient was re-evaluated approximately two months later, and no worsening of symptoms after discontinuation of medication was reported.

[0262] patient 3 The patient in this case study was a 56-year-old male with vertical gaze palsy accompanied by symmetrical dyskin-rigidity syndrome, a history of instability and falls, and impaired fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed decreased dopamine receptors, and FDG-PET of the brain showed reduced metabolism in the frontomesial and parietotemporal regions, supporting the diagnosis. There was no response to levodopa.

[0263] The patient initiated treatment with acetyl-DL-leucine, receiving a dose of 3 g per day for the first week, followed by 5 g per day thereafter. A gait analysis was performed before initiating treatment. After 17 days of treatment, medication was discontinued, and the patient was re-examined 4 days later. The patient did not report any significant improvement in gait or motor hyporigidity syndrome.

[0264] [Table 9]

[0265] The patient was re-evaluated approximately two months later, and no worsening of symptoms was reported after discontinuation of medication.

[0266] patient 4 The patient in this case study was a 76-year-old male with progressive gait disturbance, unsteady and small steps (strong tendency to fall), camptocormia, slow and hypometric saccades, blepharospasm, and impaired fine motor skills. The patient was diagnosed with progressive supranuclear palsy. MRI showed inconspicuous atrophy of the midbrain (Mickey Mouse mark). There was a slight levodopa response.

[0267] The patient initiated treatment with acetyl-DL-leucine, receiving a dose of 3 g per day for the first week, followed by 5 g per day thereafter. Gait analysis was performed before initiating treatment. After 3 weeks of treatment, medication was discontinued, and the patient was re-examined. The patient reported increased subjective stability in gait and a reduced frequency of falls. Gait analysis showed improvements in gait with respect to increased speed, max. speed, decreased step cycle length and track width, double stance, and coefficient of variation.

[0268] [Table 10]

[0269] Three months without medication, the patient reported a progression of motor hyporigidity syndrome. They experienced more frequent falls and worsened gait.

[0270] Experimental Example 12 patient 1 The patient in this case study was a 42-year-old male engineer who had suffered from dizziness and postural imbalances for almost a year.

[0271] The patient was diagnosed with lower eyelid nystagmus. The patient experienced severe impairment due to blurred vision (oscillation) caused by the nystagmus, and had difficulty reading and writing. The patient's visual acuity was 0.75 in the right eye, 0.67 in the left eye, and 0.83 in both eyes. The lower eyelid nystagmus was recorded by video-oculography. The patient also exhibited increased body sway, which was recorded by postural sway testing.

[0272] Treatment with 4-aminopyridine (Fampyra, 10 mg twice daily) for four weeks yielded no benefit.

[0273] The patient started treatment with acetyl-DL-leucine at a dose of 3g per day for one week (1g upon waking, 1g before lunch, and 1g before dinner), and then increased to a dose of 5g per day (2g upon waking, 1.5g before lunch, and 1.5g before dinner).

[0274] Ten days later, the patient reported a significant benefit, which they described as progressing slowly. The patient continued this therapeutic dose without experiencing any side effects. A temporary interruption of the medication resulted in a considerable worsening of their condition.

[0275] The patient was re-examined approximately 14 weeks after starting acetylleucine treatment, during which time the patient reported being very satisfied with the benefits. The patient's reading and writing improved significantly, due to reduced oscilloscopes and a more stable image of the visual environment. The patient was able to suppress nystagmus through fixation. Furthermore, the patient's spatial orientation improved.

[0276] Clinical examinations by two independent examiners revealed a reduction in nystagmus, and video-oculomotor recordings showed that the patient could suppress nystagmus through fixation. The patient's visual acuity was 0.83 in the right eye, 1.0 in the left eye, and 1 in both eyes.

[0277] Postural sway testing demonstrated a reduction in postural sway.

[0278] In general, this case study demonstrates improvement in the patient's symptoms, as it shows.

[0279] patient 2 The patient in this case study was diagnosed with lower eyelid nystagmus. The patient presented with postural imbalance and dizziness. The patient did not benefit from Fanpyra®.

[0280] The patient started taking acetyl-DL-leucine (3g / day in the first week; 5g / day thereafter) and subsequently showed improved walking ability, including the ability to walk much longer distances (1 hour), and improved attention. The patient's lower eyelid nystagmus also improved (recorded by video-oculomotor recording). The patient was able to partially suppress nystagmus by fixation, as assessed using a target center (a dot shown in the center of the display for 30 seconds, Figure 13A) and in complete darkness for 45 seconds using goggles covered with special glasses (Figure 13B). The results (median slow phase velocity, SPV) were as follows: Target center - horizontal: -0.02° / s, vertical: 2.41° / s; complete darkness - horizontal: 0.05° / s, vertical: 3.27° / s (Figure 13C). As shown in Figure 13A, the patient was able to minimize eye movements while fixating.

[0281] Gait analysis showed an increase in self-selected speed from 56 to 85 cm / sec and an increase in maximum walking speed from 122 to 155 cm / sec. Medication was subsequently discontinued.

[0282] Approximately one month after discontinuing acetyl-DL-leucine treatment, the patient's symptoms worsened. Gait analysis showed a decrease in self-selected speed from 85 to 72 cm / sec and a decrease in maximum walking speed from 155 to 113 cm / sec.

[0283] Experimental Example 13 patient 1 The patient in this case study was a 70-year-old woman who primarily presented with right-sided hypokinesia and tremors, antecollis, frequent falls, orthostatic dysregulation, and urge urinary incontinence.

[0284] The patient was diagnosed with multiple system atrophy, Parkinson type (MSA-P). Datscan revealed a reduction in dopamine receptors, primarily on the left side, while FDG-PET of the brain showed hypometabolism, mainly in the posterior parietal region. There was a modest levodopa response (100 / 25 mg three times daily).

[0285] The patient started taking acetyl-DL-leucine (3g / day for the first week, then 5g / day thereafter). After 3 weeks of acetyl-DL-leucine, the patient was evaluated, and no significant improvement in gait, reduction in falls, or improvement in motor hyporigidity syndrome was reported. Medication was discontinued.

[0286] Six weeks later, the patient did not report any worsening of symptoms after discontinuing the medication.

[0287] patient 2 The patient in this case study was a 78-year-old male diagnosed with multiple system atrophy, Parkinson type (MSA-P). His symptoms were characterized by progressive hypokinesia, orthostatic dysregulation, and continuous dizziness and balance disturbances. He exhibited saccadic eye movements and symmetrical rigidity of both upper limbs. Balancing on an imaginary tightrope was associated with instability and loss of balance. FDG-PET of the brain showed decreased metabolism in both the cranioparietal and occipital cortex, suggestive of Lewy body dementia.

[0288] The patient initiated treatment with acetyl-DL-leucine, receiving a dose of 3 g per day for the first week, followed by 5 g per day thereafter. The patient was examined prior to the initiation of treatment and presented with the aforementioned clinical symptoms, including very pronounced unsteady gait and dizziness.

[0289] After one month of treatment, medication was discontinued and the patient was evaluated. The patient reported a subjective improvement in dizziness, and clinical tests showed an improvement in balance on a hypothetical tightrope walk, which the patient was able to perform without any difficulty compared to previous tests. Gait analysis was performed.

[0290] One month after the end of medication, the patient reported stable symptoms. No worsening of dizziness or gait instability was reported. Gait analysis was performed.

[0291] Two months after treatment without medication, gait analysis was performed, showing a decrease in walking speed, a reduction in stride length, and a worsening of the FGA score. The patient reported a worsening of general symptoms, including progressive leg weakness and increased gait instability.

[0292] [Table 11]

[0293] patient 3 The patient in this case study was a 78-year-old male diagnosed with multiple system atrophy, Parkinson type (MSA-P). His symptoms were characterized by progressive hyporigidity syndrome, urinary incontinence, early cognitive impairment, and gait disturbance with small steps and 2-3 falls per month. Cognitive impairment was characterized by psychomotor decline and intermittent mental confusion. Datscan revealed decreased dopamine receptors, supporting the diagnosis. FDG-PET of the brain showed primarily striatal decreased metabolism. Levodopa therapy was discontinued due to side effects.

[0294] The patient initiated treatment with acetyl-DL-leucine, receiving a dose of 3 g per day for the first week, followed by 5 g per day thereafter. The patient was evaluated one month after the start of acetyl-DL-leucine administration. The patient's wife reported a significant improvement in cognitive function. Episodes of mental confusion had completely disappeared. The patient's cognitive structure appeared much clearer and more straightforward. There was no improvement in walking ability. The patient's wife supported the continuation of the medication.

[0295] Experimental Example 14 The patient in this case study was a 45-year-old male diagnosed with spinocerebellar ataxia 28 (SCA 28). Genetic testing revealed a known pathogenic variant in AFG3L2. The patient's symptoms were characterized by a progressive cerebellar syndrome that had developed since age 30, which was also characterized by slurred speech, unsteady gait, balance disorders, and dizziness. The patient's father and grandmother also suffered from similar symptoms. The patient exhibited oculomotor and ataxic disorders in coordination tests, ataxic gait, blunt speech, exaggerated lower limb reflexes, lower limb spasticity, and a positive left-sided Babinski sign. cMRI showed marked cerebellar atrophy.

[0296] The patient initiated treatment with acetyl-DL-leucine at a dose of 5 g per day. Gait analysis was performed before starting treatment. Approximately one month after treatment, medication was discontinued, and the patient was evaluated. The patient reported improvement in symptoms, particularly a reduction (almost complete disappearance) of dizziness, and a more stable gait. The patient reported that he was no longer walking like a robot and could climb stairs without using the handrail. Gait analysis was performed, showing improvement in parameters.

[0297] [Table 12]

[0298] Experimental Example 15 Patients 1 and 2 The patients in this case study were two female sisters, aged 24 (Patient 1) and 19 (Patient 2). Both patients suffered from ataxia telangiectasia.

[0299] Patient 1 exhibited developmental milestone delays. The patient did not walk until age 2 and had signs and symptoms of cerebellar ataxia, including seizures, along with marked distal generalized hypertonia and telangiectasia in the eyes, ears, and chest. The diagnosis was established at age 9. Patient 1's oculomotor function showed downbeat nystagmus with gaze to the left and gaze straight-ahead (larger than right), gaze-holding nystagmus upward, vertical and horizontal saccadic smooth pursuit, and hypometric saccades horizontally and vertically, but with restricted motility upward.

[0300] Prior to the initiation of treatment, Patient 1's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 22 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking test (8MW): 21.8 seconds (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 90.2 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 125.8 seconds (9-Hole Pegboard Test Dominant) MW PATA Word Test: 12.5 Visual analog scale (patient assessment): 99

[0301] The results of the video eye movement recording method were as follows: [Table 13]

[0302] Patient 1 initiated treatment with acetyl-DL-leucine (5g / day) after the examination. One month after treatment, the patient was re-evaluated. The caregiver reported improvements in speech and gait. The patient himself did not feel any change. The examination showed a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patient were as follows: Average 8-meter walking test (8MW): 18.5 seconds (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 77.9 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 101.3 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 13 Visual analog scale (as assessed by patients): 85

[0303] The results of the video eye movement recording method were as follows: [Table 14]

[0304] A subset of SARA and SCAFI in patient 1 improved after treatment, and video eye movement recordings showed significant improvement in fixation stability and a reduction in the intensity of lower eyelid-directed nystagmus.

[0305] Patient 2 presented with delayed developmental milestones, seizures at age 1, generalized hypotonia, contractures of low extremities with symmetrical equinovarus, areflexia, acute lymphoblastic leukemia at age 3, slightly enlarged spleen, hypercholesterolemia, hypochromatic microcytic anemia, pigmented naevi, and vitiligo. The first symptoms were noticed by the patient's parents at age 15 months. Patient 2's eye movement function exhibited square wave jerks, gaze-holding nystagmus left greater than right with a vertical component, downbeat nystagmus, saccadic smooth pursuit, vertical gaze palsy upward greater than downward, and impaired convergence.

[0306] Prior to the initiation of treatment, Patient 2's examination showed a Scale for Assessment and Rating of Ataxia (SARA) score of 28.5 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking test (8MW): Cannot be performed without support. (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 300 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 299.2 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 13.5 Visual analog scale (as assessed by patients): 45

[0307] The results of the video eye movement recording method were as follows: [Table 15]

[0308] Patient 2 initiated treatment with acetyl-DL-leucine (5g / day) after the examination. One month after treatment, the patient was re-evaluated. Caregivers reported improvements in fine motor skills, hand tremors, and speech. The patient himself reported no benefit. The examination showed a Scale for Assessment and Rating of Ataxia (SARA) score of 23.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patient were as follows: Average 8-meter walking test (8MW): Cannot be done without support. (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 300 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 300 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 14 Visual analog scale (as assessed by patients): 80

[0309] The results of the video eye movement recording method were as follows: [Table 16]

[0310] Video eye movement recording showed significant improvements in fixation stability and nystagmus intensity in patient 2.

[0311] patient 3 The patient in this case study was a 19-year-old woman who had suffered from ataxia telangiectasia since childhood. The patient presented with delayed motor development, signs and symptoms of cerebellar ataxia, pronounced axial hypotonia with acral hypertonia, severe contractures of feet with orthopedic deformities such as equinus and bilateral transversoplanus that limited wheelchair use, dysdiadochokinesis, and areflexia of low extremities with decreased proprioceptive perception. - The patient had non-Hodgkin lymphoma, polymorphic MTHFR (C677T), lymphangioma of the lower lip, cholecystolithiasis, dilated cardiomyopathy, pigmented nevi, thoraco-lumbar kyphoscoliosis, and scleral teleangiectasias in both eyes.

[0312] The patient's eye movement function included gaze-holding nystagmus to the right and left, saccadic eye movements, slow saccades in all directions, especially horizontally, a pathological vestibulo-ocular reflex accompanied by corrective catch-up saccades, and pathological visual-fixation suppression accompanied by a vestibulo-ocular reflex.

[0313] Prior to the initiation of treatment, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 23 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking test (8MW): Not possible (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 150 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 161.6 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 14 Visual analog scale (to be assessed by the patient): 80

[0314] The results of the video eye movement recording method were as follows: [Table 17]

[0315] The patient initiated treatment with acetyl-DL-leucine (5g / day) approximately 6 months after the examination. The patient was re-evaluated when treatment slightly exceeded 7 months. Both the caregiver and the patient reported an overall improvement in health without further specification. The examination yielded a Scale for Assessment and Rating of Ataxia (SARA) score of 21.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patient were as follows: Average 8-meter walking test (8MW): Not possible (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 124.5 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 147.5 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 10 Visual analog scale (as assessed by patients): 80

[0316] The results of the video eye movement recording method were as follows: [Table 18]

[0317] Patients showed slight improvement in SARA and SCAFI subset 9HPT, as well as significant improvement in fixation stability and a reduction in the intensity of gaze-holding nystagmus at all positions.

[0318] patient 4 The patient in this case study was a 15-year-old female who had suffered from telangiectatic ataxia since the age of 4. From the age of 7, the patient presented with signs and symptoms of severe cerebellar ataxia, including fine motor dysfunction, hypotonia with anomalies, muscular atrophy, and plantar flexion with separate contractures. The patient was wheelchair-bound but could walk with constant support. The patient had severe hemolytic anemia, hypogammaglobulinemia, scleral and thoracic telangiectasia, and secondary Cushing's syndrome due to corticosteroid use, but was suspected of having central nervous system non-Hodgkin lymphoma.

[0319] The patient's eye movement function exhibited slow upward deviation of the eyes, left beating nystagmus in the central position, horizontally with a downbeating component, gaze-holding nystagmus in all directions, and startle with sudden head movement.

[0320] Prior to the initiation of treatment, the patient's examination showed a Scale for Assessment and Rating of Ataxia (SARA) score of 23.5 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter walking test (8MW): Not possible (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 124.5 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 52.3 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 14 Visual analog scale (as to be assessed by the patient): 70

[0321] The results of the video eye movement recording method were as follows: [Table 19]

[0322] The patient initiated treatment with acetyl-DL-leucine (5g / day) after the examination. The patient was re-evaluated slightly over one month after treatment. The patient and their mother reported improvements in handwriting, particularly in hand tremor and fine motor skills. The patient also reported easier drinking and no longer needing a straw. The family described improved gait, noting increased stability and requiring less support. The examination yielded a Scale for Assessment and Rating of Ataxia (SARA) score of 18.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patient were as follows: Average 8-meter walking test (8MW): Not possible (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 93.5 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 101.7 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 15.5 Visual analog scale (as assessed by patients): 70

[0323] The results of the video eye movement recording were as follows: [Table 20]

[0324] The patient showed improvement in SARA and SCAFI subset 9HPT in the dominant hand. Video eye movement recording showed a decrease in the intensity of spontaneous and gaze-holding nystagmus and a general improvement in fixation stability at all positions.

[0325] patient 5 The patient in this case study was a 10-year-old boy who had suffered from ataxia telangiectasia since infancy. - The child had delayed psychomotor development, unsteady gait at 14 months of age with a high incidence of falls, signs and symptoms of severe cerebellar ataxia, paralytic dysarthria and functional dysarthria, rare head tremors, slow psychomotor tempo, hypotonia with muscular atrophy and hyporeflexia, anteflexia with kyphosis in the thoracal area, transverse flatfoot, scapullae allatae, parasomnia with pavor nocturnus, and autism, but also, - The patient had severe immunosuppression, telangiectasias on the soft palate, scleral issues, incontinence, and an asthenic habitus.

[0326] The patient was restrained in a wheelchair but was able to perform several steps with strong, continuous support. The patient's oculomotor function showed oculomotor apraxia with pronounced head anteflexia, vertical fixation palsy with "summary" head and eye movements and slow vertical saccadic movements (saccades) when turning right and left, slow horizontal saccadic movements (saccades) to the left, saccadic oculomotor palsy to the right, restricted eye movements, particularly vertically, and fixation instability in all positions.

[0327] Prior to the initiation of treatment, the patient's examination revealed a Scale for Assessment and Rating of Ataxia (SARA) score of 24.5 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter Walking Test (8MW): Unable to walk without constant support. MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 102.7 seconds MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 116.8 seconds MW PATA Word Test: 6 Visual analog scale (as assessed by the patient): 90

[0328] The results of the video eye movement recording method were as follows: [Table 21]

[0329] The patient began treatment with acetyl-DL-leucine (5g / day) after the examination. Approximately one month after starting treatment, the patient was re-evaluated. The patient's mother stated that his walking stability had improved significantly, whereas before treatment he would constantly fall backward and had to be partially "carried." During medication, he was able to walk with only the help of a caregiver's hand.

[0330] Fine motor function, hand tremor intensity, and body control improved. The improvement in fine motor function was independently reflected in daily activities such as eating and drinking. The patient gained 1.5 kg in weight and had an increased appetite. The examination yielded a Scale for Assessment and Rating of Ataxia (SARA) score of 20.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patient were as follows: Average 8-meter Walking Test (8MW): Unable to walk without support. MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 103.6 seconds MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 88.8 seconds MW PATA Word Test: 7.5 Visual analog scale (as assessed by patients): 80

[0331] The results of the video eye movement recording method were as follows: [Table 22]

[0332] Nearly seven months after treatment, the patient was re-evaluated. The patient's mother described a significantly more stable gait, a finding that had remained consistent since the initial post-treatment assessment. The patient had improved concentration and speech. The patient was able to stand on their own and was generally more independent in daily activities. The patient had an improved appetite, gained an additional 3 kg, and showed improved muscle strength.

[0333] The examination yielded a Scale for Assessment and Rating of Ataxia (SARA) score of 17.5 / 40. The results of the patient's Spinocerebellar Ataxia Functional Index (SCAFI) analysis were as follows: Average 8-meter Walking Test (8MW): 15.3 seconds (with hands clasped) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 92.4 seconds MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 98.3 seconds MW PATA Word Test: 11 Visual analog scale (as assessed by the patient): 100

[0334] The patient was re-evaluated slightly over a year after treatment and showed improved social interaction, activity, and agility. The patient's parents reported improvement in incontinence. The patient developed recurrent frontal localized pain accompanied by vomiting in the morning. Based on family history, the localized pain was suspected to be due to childhood migraine.

[0335] The examination included a Scale for Assessment and Rating of Ataxia (SARA) score of 16.5 / 40. The results of the Spinocerebellar Ataxia Functional Index (SCAFI) analysis of the patients were as follows: Average 8-meter walking test (8MW): 13.9 seconds (with mother holding his hand, he can walk on his own) (8-meter Walking Test) MW 9-Hole Pegboard Test Dominant (9HPTD) (Right): 95.6 seconds (9-Hole Pegboard Test Dominant) MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 127.6 seconds (9-Hole Pegboard Test Non-Dominant) MW PATA Word Test: 14.5 Visual analog scale (as to be assessed by the patient): 95

[0336] Treatment with acetyl-DL-leucine resulted in improved SARA and SCAFI subtest scores, improved quality of life, generally improved fixation stability, and reduced intensity of spontaneous and fixation-holding nystagmus, particularly in the vertical plane (after 1 month).

[0337] patient 6 The patient in this case study was a 10-year-old female with ataxia telangiectasia who presented with ataxic gait and stance, fine motor dysfunction with hand tremors, dysphagia and speech disorders, oculomotor disorders, and problems with cognitive function and concentration. The first symptoms were observed at age 1.

[0338] Following baseline examinations, patients initiated acetyl-DL-leucine therapy at 1.5 g / day for the first week, followed by 3 g / day from the second week onward. Patients were evaluated at 1 month and 6 months of treatment, respectively. At 1 month of treatment, patients showed increased fine motor skills with reduced hand tremor, improved postural stability and gait, increased speech, and increased confidence. At 6 months of treatment, patients had a stable overall condition, stable gait and stance, and improved handwriting. The patient, however, suffered from anxiety, which would be expected to negatively impact their response.

[0339] The patients' SARA and SCAFI scores in each assessment were as follows: [Table 23]

[0340] Experimental Example 16 The patient in this case study was a woman in her early 60s who was genetically diagnosed with spinocerebellar ataxia (SCA) 1. Prior to treatment, the patient had severe problems with speaking and swallowing, bilateral arm tremors, and moderate ataxia and spasticity in her stance and gait. The patient also had sleep disturbances.

[0341] After three weeks of treatment with acetyl-DL-leucine (5g / day), all symptoms significantly improved, as further demonstrated by clinical examinations including spasticity and impaired eye movement function.

[0342] After three months, medication was discontinued. Two weeks later, the severity of signs and symptoms was the same as before treatment. Treatment was restarted, and the patient has continued to maintain the same dosage without side effects for more than two years.

[0343] The patient's daughter reported a significant progression of the disease over time with persistent symptomatic effects, but anecdotally reported that long-term symptomatic efficacy was observed from the treatment.

[0344] Experimental Example 17 The patient in this case study was a 70-year-old woman with unsteady gait and frequent falls, nocturnal hallucinations, and REM sleep disturbances. The patient had symmetrical motion disorder-rigidity syndrome with attentive and aware wandering and impaired fine motor skills.

[0345] The patient was diagnosed with Lewy body dementia. Brain FDG-PET showed synaptic dysfunction in the parietal and occipital lobes, and DATscan showed degeneration of presynaptic dopamine transporters, supporting the diagnosis. Treatment with levodopa 100 mg four times daily and quetiapine 25 mg at night improved the patient's symptoms.

[0346] The patient started taking acetyl-leucine (3g / day for 1 week; then 5g / day) and was evaluated after 4 weeks. The patient reported increased fatigue and worsening balance and speech. The dosage was reduced to 3g / day, and the patient was instructed to discontinue the medication after approximately 2 weeks.

[0347] Patients were re-evaluated approximately one month after discontinuing medication, and no improvement in symptoms due to the reduction in dosage or worsening of symptoms after discontinuation was reported.

[0348] [Table 24]

[0349] Experimental Example 18 In this case study, four patients (male brothers) had, but were subsequently diagnosed with, ataxia with oculomotor apraxia type 4. The three older brothers were 12, 11, and 10 years old at the onset of symptoms, respectively. The patients' mother reported that the three older brothers were able to walk in makeshift ways before initiating acetyl-DL-leucine treatment by age 15 / 16. The older brothers started acetyl-leucine treatment at ages 25, 23, and 19, respectively, and received treatment for approximately four years. There is no available long-term clinical data for these three patients.

[0350] The youngest sibling was 11 years old at the onset of the disease. He began treatment with acetyl-DL-leucine at age 13. During treatment, the youngest sibling was unable to walk by makeshift means until nearly age 18, as reported by the patient's mother. The patient's mother also reported that the youngest sibling had improved fine motor skills and improved speech at each age compared to his older siblings. There is no available long-term clinical data for the youngest sibling.

[0351] Experimental Example 19 The severity of NPC patients may be quantified by assigning a clinical severity score (CSS) to each parameter, which is determined by evaluating various parameters of the disease and assigning a score of 5 (higher score = higher severity). See Yanjanin et al., "Linear clinical progression independent of age of onset in Niemann-Pick disease type C," Am J Med Genet Part B 153B:132-140. In untreated patients, disease progression appears linear, so it is possible to predict how the CSS will change over time in individuals in a typical manner. For example, if patient A progressed 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 patient B has a CSS of 8 at age 2, their ASIS would be 4. Each year, the patient is expected to progress by 4 CSS points, and by age 4, their CSS will be 16. If therapeutic intervention slows or halts disease progression, the patient is expected to have a lower ASIS score after such treatment than at baseline.

[0352] Ten NPC patients received acetylleucine at a dose of 4.5 g / day over an extended period. CSS was determined at baseline and at various time points for eye movements, gait, speech, swallowing, fine motor skills, cognitive function, memory, and seizures. The total CSS at baseline and at each such time point was calculated by adding the individual CSS values ​​for each parameter (eye movements, gait, etc.). As shown in Table 25, the number of days after the start of treatment at which CSS was assessed varied among patients.

[0353] [Table 25]

[0354] Tables 26-34 below show the CSS for overall, eye movement, gait, speech, swallowing, fine motor skills, cognitive abilities, memory, and seizures, respectively.

[0355] [Table 26]

[0356] [Table 27]

[0357] [Table 28]

[0358] [Table 29]

[0359] [Table 30]

[0360] [Table 31]

[0361] [Table 32]

[0362] [Table 33]

[0363] [Table 34]

[0364] Baseline and ASIS at each time point were calculated using each patient's CSS and age at assessment. The overall ASIS for each patient at each time point is shown in Table 35 below.

[0365] [Table 35]

[0366] As shown in Table 26 and Figure 10A, none of the 10 patients showed an overall increase in CSS over the course of the experiment. Patient 6 showed an increase in 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 constant CSS throughout the course of the experiment, but showed no disease progression in these individuals. Six of the 10 patients (patients 1, 3, 4, 8, 9, and 10) showed a decrease in CSS throughout the course of the experiment, which indicates no disease progression and, in fact, a decrease in severity. Improvements were seen in various subscores: Patient 1: gait; Patient 3: fine motor skills; Patient 4: gait and speech; Patient 8: eye movement and fine motor skills; Patient 9: memory; Patient 10: cognition. The data presented in Figures 11A to 11J show each patient's CSS subscore in the form of bar graphs.

[0367] As shown in Table 35 and Figure 10B, all 10 patients showed a decrease in ASIS during treatment compared to baseline ASIS. In patients 2, 5, 6, and 7, CSS remained the same as age increased, resulting in a slight decrease in ASIS. In patients 1, 3, 4, 8, 9, and 10, the decrease in ASIS was greater due to a decrease in CSS as age increased.

[0368] Experimental Example 20 As described herein, the Niemann-Pick disease type C (NPC) mouse model shares many pathological features with Alzheimer's disease (AD). Wild-type NPC1 - / - Mice were treated with acetyl-dl-leucine (0.1 g / kg body weight daily) from 3 weeks of age. Mice were sacrificed at 8 weeks of age. Wild-type and untreated wild-type NPC1 mice were used. - / - Mouse, and AL-treated wild-type NPC1 - / - In mice, the levels of total amyloid precursor protein (APP) and amyloid precursor protein C-terminal fragments (APP-CTF) in the cerebellum were evaluated. The levels of microtubule-associated protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate were also evaluated in wild-type and untreated wild-type NPC1 mice. - / - Mouse, and AL-treated wild-type NPC1 - / - The level of tubulin loading control in mice was evaluated.

[0369] The APP-CTF data are shown in Figure 12A. The data reproduced the aforementioned accumulation of APP-CTF (APP-CTFs) in the brains of NPC1 mice. Treatment with acetyl-dl-leucine was associated with a decrease in APP-CTF (APP-CTFs).

[0370] LC3-II data are shown in Figure 12B. The data replicated the aforementioned accumulation of LC3-II in the brains of NPC1 mice. Treatment with acetyl-dl-leucine was associated with a decrease in LC3-II, which indicates a partial recovery of the autophagic flux.

[0371] conclusion Acetyl-leucine treatment was associated with improvement in AD symptoms in the brains of NPC1 mice. [1] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in a method of treating one or more symptoms of a neurodegenerative disease or neurodegenerative disease in subjects where there is a need for such treatment, provided that the neurodegenerative disease is not cerebellar ataxia or Niemann-Pick disease type C. [2] Given that neurodegenerative diseases are associated with lysosomal dysfunction, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method described in [1] above. [3] Neurodegenerative diseases associated with lysosomal dysfunction are selected from alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Canavan disease, frontotemporal lobar degeneration, Huntington's disease, multiple system atrophy (MSA-P / MSA-C), multiple sclerosis, narcolepsy, Parkinson's disease, Smith-Lemle-Oppitz syndrome (SLOS) (congenital cholesterol production disorder), Tangier's disease, Pelizaeus-Merzbacher disease, Pick's disease, frontotemporal dementia with parkinsonism, prion diseases, progressive supranuclear palsy, spinal muscular atrophy, and neurodegenerative lysosomal storage disorders (LSDs), wherein acetyl-leucine or a pharmaceutically acceptable salt thereof is used in the method described in [2] above. [4] A neurodegenerative disease associated with lysosomal dysfunction is selected from ALS, MSA-P, MSA-C, frontotemporal dementia with parkinsonism, progressive supranuclear palsy, and Alzheimer's disease, and acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method described in [3] above. [5] The neurodegenerative disease is selected from Alexander disease, Alpers disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, HIV-associated neurodementia, Kennedy disease, neuroborreliosis, primary lateral sclerosis, Refsum disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, proximal muscle-dominant hereditary motor sensory neuropathy, hedgehog stagger syndrome (WHS), progressive muscular atrophy (Duchenne-Alain type muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), cerebrovascular parkinson's disease, lower body parkinson's disease, and cerebellar lower eyelid nystagmus, and acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method described in [1] above. [6] Where the neurodegenerative disease is motor neuron disease, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method described in [1] above. [7] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in methods of treating neurodegenerative diseases in subjects who are asymptomatic but who require such treatment. [8] If the subject is found to have a genetic and / or biochemical marker for a neurodegenerative disease, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in the method described in [7] above. [9] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in a method of delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest differently due to typical disease progression.

[10] A method for treating one or more symptoms of neurodegenerative disease or neurodegenerative disease in a subject in need, comprising administering a therapeutically effective amount of acetyl-leucine to the subject in need for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years, for use in a method, wherein acetyl-leucine or a pharmaceutically acceptable salt thereof.

[11] A method for use in a method that slows the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease over time compared to the typical progression of the disease, comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years, wherein acetyl-leucine or a pharmaceutically acceptable salt thereof.

[12] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in a method for reversing the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease over time, comprising administering a therapeutically effective amount of acetyl leucine to a subject in need for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years.

[13] A method for improving biochemical markers of neurodegenerative disease over time in subjects in need, comprising administering a therapeutically effective amount of acetyl-leucine to subjects in need 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, for use in a method, wherein acetyl-leucine or a pharmaceutically acceptable salt thereof.

[14] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in the method described in

[13] above, wherein the biochemical marker is the increased amount of lysosomes.

[15] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in any of the above [1] to

[14] , comprising initiating administration of a therapeutically effective amount of acetyl leucine to a subject in need, when the subject is asymptomatic.

[16] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in the method described above

[15] , wherein the first dose is administered after the subject is found to have a genetic and / or biochemical marker for a neurodegenerative disease.

[17] A method comprising administering a therapeutically effective amount of acetyl-leucine to a subject in need for a period selected from at least about three months, at least about six months, at least about one year, at least about two years, and at least about five years, for use in any of the methods described in [1] to [9] above, wherein acetyl-leucine or a pharmaceutically acceptable salt thereof.

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

[17] , wherein acetyl-leucine is acetyl-DL-leucine.

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

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

[20] A method comprising administering acetyl-leucine to a subject in need in a therapeutically effective amount of approximately 1 g to 15 g per day, approximately 1 g to 10 g per day, approximately 1.5 g to 7 g per day, approximately 4 g to 6 g per day, or approximately 4 g to 5 g per day, wherein acetyl-leucine or a pharmaceutically acceptable salt thereof for use in any of the methods described in [1] to [9] above. [twenty one] A therapeutically effective amount of acetyl-leucine is approximately 1 g to 15 g per day, approximately 1 g to 10 g per day, approximately 1.5 g to 7 g per day, approximately 4 g to 6 g per day, or approximately 4 g to 5 g per day, for use in any of the above

[10] to

[17] , acetyl-leucine or a pharmaceutically acceptable salt thereof. [twenty two] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in any of the above [7] to

[14] methods relating to neurodegenerative diseases associated with lysosomal dysfunction. [twenty three] Neurodegenerative diseases associated with lysosomal dysfunction include alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Canavan disease, frontotemporal lobar degeneration, Huntington's disease, multiple system atrophy (MSA-P / MSA-C), multiple sclerosis, narcolepsy, Parkinson's disease, Smith-Lemle-Oppitz syndrome (SLOS) (congenital cholesterol production disorder), Tangier's disease, Pelizaeus-Merzbacher disease, Pick's disease, frontotemporal dementia with Parkinson's disease, prion diseases, progressive supranuclear palsy, spinal muscular atrophy, neurodegenerative lysosomal storage disorder (LSD), spinocerebellar ataxia (SCA)2, spinocerebellar ataxia (SCA)2, spinocerebellar ataxia (SCA)3 (Machado-Joseph disease), and spinal... Acetyl leucine or a pharmaceutically acceptable salt thereof for use in the method described in

[22] above, selected from cerebral ataxia (SCA) 6, spinocerebellar ataxia (SCA) 7, spinocerebellar ataxia (SCA) 17, dentatorubral-pallidoluysian atrophy, Charlevois-Saganay's autosomal recessive convulsive ataxia (ARSACS), autosomal recessive cerebellar ataxia type 1 (Bose's recessive ataxia (RAB), SYNE-1 mutation), autosomal recessive cerebellar ataxia type 2 (spinocerebellar ataxia autosomal recessive 9, SCAR9), ataxia with vitamin E deficiency (AVED), telangiectatic ataxia (Louis-Barr disease), Friedreich's ataxia (FRDA), and ataxia with coenzyme Q10 deficiency. [twenty four] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in the method described above

[23] , wherein the neurodegenerative disease associated with lysosomal dysfunction is selected from ALS, MSA-P, MSA-C, frontotemporal dementia with parkinsonism, progressive supranuclear palsy, Alzheimer's disease, SCA-1, and ataxia telangiectasia. [twenty five] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in any of the above [7] to

[14] , wherein the neurodegenerative disease is selected from Alexander disease, Alper's disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, HIV-associated neurodementia, Kennedy disease, neuroborreliosis, primary lateral sclerosis, Refsum disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, proximal muscle-dominant hereditary sensorimotor neuropathy, hedgehog stagger syndrome (WHS), progressive muscular atrophy (Duchenne-Alain type muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), vascular parkinsonian syndrome, lower body parkinson's disease, cerebellar ataxia, and cerebellar lower eyelid nystagmus.

[26] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in any of the above [7] to

[14] methods, wherein the neurodegenerative disease is motor neuron disease.

[27] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in a method of reducing the severity of a neurodegenerative disease or reducing or eliminating the severity of one or more pre-existing symptoms associated with a neurodegenerative disease, in subjects where the neurodegenerative disease is not cerebellar ataxia or Niemann-Pick disease type C, where such a method is needed.

[28] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in a method for providing neuroprotective effects in a subject having, suspected of having, or potentially having a neurodegenerative disease, 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.

[29] Acetyl leucine or a pharmaceutically acceptable salt thereof for use in any of the above [7], [9] to

[13] , and

[28] , wherein the neurodegenerative disease is selected from ALS, MSA-P, MSA-C, frontotemporal dementia with parkinsonism, progressive supranuclear palsy, Alzheimer's disease, SCA 1, ataxia with telangiectasia, cerebellar nystagmus, SCA 28, ataxia type 4 with oculomotor apraxia (AOA4), and corticobasal degeneration.

Claims

1. A pharmaceutical composition for use in providing neuroprotection to a subject suffering from, suspected of suffering from, or at risk of suffering from, a neurodegenerative disease characterized by ataxia with oculomotor apraxia type 4, comprising as an active ingredient acetylleucine or a pharmaceutically acceptable salt thereof, wherein a therapeutically effective amount of acetylleucine is administered to the subject for a period selected from at least one year, at least two years, and at least five years.

2. A pharmaceutical composition according to claim 1, wherein use comprises initiating the administration of a therapeutically effective amount of acetylleucine to a subject in need when the subject is asymptomatic.

3. A pharmaceutical composition according to claim 2, wherein the first administration is performed after it has been found that the subject has genetic and / or biochemical markers for a neurodegenerative disease.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein acetylleucine is acetyl-DL-leucine.

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein acetylleucine has an enantiomer-excess L-enantiomer or D-enantiomer.

6. A pharmaceutical composition according to any one of claims 1 to 3, wherein use comprises administering acetylleucine to a subject in need in a therapeutically effective amount of 1 g to 15 g per day, 1 g to 10 g per day, 1.5 g to 7 g per day, 4 g to 6 g per day, or 4 g to 5 g per day.

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