阅读说明：本技术 神经退行性疾病的治疗剂 (Therapeutic agent for neurodegenerative disease ) 是由 M·法克拓尔 于 2018-02-15 设计创作，主要内容包括：本公开提供了治疗神经退行性疾病的方法,其包括施用亮氨酸、乙酰-亮氨酸或其药学上可接受的盐。(The present disclosure provides methods of treating neurodegenerative diseases comprising administering leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof.)

1. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of treating Restless Legs Syndrome (RLS) in a subject suffering from a neurodegenerative disease.

2. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to claim 1, wherein the neurodegenerative disease is parkinsonism.

3. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to claim 1, wherein the neurodegenerative disease is a motor neuron disease.

4. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to claim 1, wherein the neurodegenerative disease is parkinson's disease.

5. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to claim 1, wherein said neurodegenerative disease is associated with dysfunction of the dopaminergic system.

6. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method of treating Restless Legs Syndrome (RLS) in a subject in need thereof, wherein the RLS is a neurodegenerative disease.

7. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to any one of claims 1 to 6, wherein the leucine is DL-leucine or the acetyl-leucine is acetyl-DL-leucine.

8. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof for use in a method according to any one of claims 1 to 6, wherein the leucine or acetyl-leucine has an enantiomeric excess of the L-enantiomer or the D-enantiomer.

9. The leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof for use in a method of any one of claims 1 to 8, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the acetyl-leucine in the range of from about 1 g/day to about 15 g/day, from about 1 g/day to about 10 g/day, from about 1.5 g/day to about 7 g/day, from about 4 g/day to about 6 g/day, or from about 4 g/day to about 5 g/day.

Drawings

FIG. 1 shows treated (FIG. 1A) and untreated (FIG. 1B)9 weeks of age Npc1^-/-Photographs of the mice.

FIGS. 2A and 2B show Npc1 with and without acetyl-DL-leucine treatment from weaning^-/-Mouse and wild type (Npc 1)^+/+) Weight data for mice.

FIGS. 3A-3G show Npc1 with and without acetyl-DL-leucine treatment from weaning^-/-Mouse and wild type (Npc 1)^+/+) Gait analysis data of mice. For example, fig. 3A-3C show diagonal support, stride frequency, and stride sequence data, respectively. Figures 3D and 3E show the Fore Paw (FP) data (mean and step period in figure D; duty cycle in figure E). FIGS. 3F and 3G show Hind Paw (HP) data (in FIG. F, forMean number of standings and step period; duty cycle in graph G).

FIGS. 4A-4H show Npc1 with and without acetyl-DL-leucine treatment from weaning^-/-Mouse and wild type (Npc 1)^+/+) Motor function analysis data compared to mice. Center upright, mobility, upright, and front-to-back (FR) counts are shown in fig. 4A-4D, respectively. The activity time, movement time, standing time and total manual standing count are shown in fig. 4E-4H, respectively.

FIG. 5 shows that treatment with acetyl-DL-leucine (0.1g/kg, 3 weeks old) correlates with a small but statistically significant increase in longevity of Npc 1-/-mice.

Figures 6A and 6B show the reduction of lysosomal volume in non-neuronal NPC cells after treatment with acetyl-DL-leucine. FIGS. 6C-6H show the effect of treatment with acetyl-DL-leucine on lysosomal volume in fibroblasts from NPA, MLII, MPS IIIB, aspartylglucamine urine, MLIIIA and MPS VII patients, respectively.

Figure 7A shows survival curves representing mortality in untreated or acetyl-leucine treated wild type and Sandhoff mice. Figure 7B shows the transrod fraction (Bar cross score) of untreated and acetyl-leucine treated Sandhoff model mice. Figure 7C shows the step cycle time of untreated and acetyl-leucine treated Sandhoff mice evaluated at 12 weeks of age.

FIGS. 8A-8C show the effect of treatment with acetyl-DL-leucine on the level of Glycosphingolipids (GSLs) in fibroblasts of GM2 gangliosidosis patients (Tay-saxophone disease, Sandhoff disease, and AB variants of Tay-saxophone disease, respectively).

Fig. 9 shows a gait analysis matrix for a 75 year old male patient diagnosed with corticobasal degeneration syndrome before and during treatment with acetyl-leucine, where fewer pink regions in the matrix indicate an improvement compared to before treatment.

Figures 10A and 10B show the effect of treatment with acetyl-DL-leucine on the total Clinical Severity Score (CSS) and total annual severity delta score (ASIS) of 10 NPC patients over time, respectively.

FIGS. 11A-11J show the effect of treatment with acetyl-DL-leucine on CSS sub-score for each of 10 NPC patients over time.

FIGS. 12A and 12B show treatment of wild-type NPC1 with acetyl-DL-leucine, respectively^-/-Effect of mice on levels of the C-terminal fragment of amyloid precursor protein (APP-CTF) and microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC 3-II).

Figures 13A-13C show that patients diagnosed with the nystagmus syndrome can partially suppress nystagmus by visual fixation after treatment with acetyl-DL-leucine.

FIG. 14 shows the reduction of lysosomal volume in NPC Chinese Hamster Ovary (CHO) cells after treatment with acetyl-DL-leucine, acetyl-D-leucine, acetyl-L-leucine, DL-leucine, D-leucine and L-leucine, respectively.

Detailed Description

Acetyl-leucine (acetyl-DL-leucine) and its salts in racemic form are effective in the treatment of vertigo of various origins, in particular vertigo of Meniere's disease (Meniere's vertigo) and inflammation (vestibular neuritis) or of toxic origin. For example, acetyl-leucine is marketed by Pierre Fabre medical in racemic form as an anti-glare drug under the nameReported by different authorsClinical results indicate an improvement in vertigo symptoms in more than 95% of cases, including the disappearance of vertigo attacks.

acetyl-DL-leucine has been used in france for the treatment of acute vertigo since 1957 and has excellent safety, but its long-term safety in long-term use has not been established. Despite numerous assumptions, including the stabilization of membrane potential, its pharmacological and electrophysiological modes of action remain unclear. (Vibert et al (2001) Eur J Neurosci; 13(4): 735-48; Ferber-Viart et al (2009) Audio neurool; 14(1): 17-25). The FDG- μ PET study in a rat model of acute unilateral labyrinectomy (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 vestibular cerebellar activation and posterolateral thalamic inactivation (Gunther et al (2015) PLoS One; 10(3): e 0120891). The symptomatic improvement of cerebellar ataxia with acetyl-DL-leucine is shown in the series of cases in cerebellar patients (Strupp et al (2013) J Neurol; 260(10): 2556-61). No benefit was seen in another series of cases (Pelz et al (2015) J Neurol; 262(5): 1373-5). Quantitative gait analysis showed that acetyl-DL-leucine improved temporal gait variability in patients with cerebellar ataxia (Schniepp et al (2015) Cerebellum; 3: 8). In a one month study involving 12 Niemann-pick disease type C (NPC) patients, improvement in the symptoms of ataxia was shown (Bremova et al (2015) Neurology; 85(16): 1368-75). In addition, PET studies in patients with ataxia who have taken acetyl-DL-leucine show increased metabolism in the middle and lower brainstem of responders (Becker-Bense et al (2015) Abstract EAN).

However, acetyl-leucine is not known to be able to treat neurodegenerative diseases, which usually progress in the course of years to decades. The present disclosure surprisingly shows that acetyl-leucine or a pharmaceutically acceptable salt thereof can be used in a method of treating a neurodegenerative disease in a subject in need thereof by: for example, delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest as typical disease progression, and/or delaying or reversing the progression (e.g., long-term progression) of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease as compared to typical disease progression.

As presented by the present disclosure, it has also been found that leucine or a pharmaceutically acceptable salt thereof may be used in a method of treating a neurodegenerative disease in a subject in need thereof by: for example, delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest as typical disease progression, and/or delaying or reversing the progression (e.g., long-term progression) of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease as compared to typical disease progression.

These exemplary applications of the present disclosure, as well as the other applications described herein, are entirely unexpected, as these benefits have not been previously observed and cannot be deduced from the teachings of the prior art. As demonstrated by the examples demonstrating effectiveness for a wide range of neurodegenerative diseases, the inventors believe that leucine and acetyl-leucine act as neuroprotective agents, thus inhibiting neurodegeneration that would otherwise be expected to occur. In addition, many neurodegenerative diseases are associated with defects in lysosomal storage, and lysosomal dysfunction (e.g., abnormally high levels of lysosomal storage) may be the cause of neuronal dysfunction and death. As demonstrated in the examples, but without wishing to be bound by any particular theory, the inventors have discovered, among other things, that leucine and acetyl-leucine can improve cellular dysfunction (e.g., by reducing lysosomal volume to control values) and provide neuroprotection.

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

As used herein, a "subject" can be a vertebrate, a mammal, or a domestic animal. Thus, the compositions of the present disclosure may be used to treat any mammal, such as a farm animal (e.g., a horse, cow, sheep, or pig), a pet (e.g., a cat, dog, rabbit, or guinea pig), a laboratory animal (e.g., a mouse or rat), or may be used for other veterinary applications. In one embodiment, the subject is a human.

As used herein, "neurodegenerative disease" refers to any condition that affects neurons and involves progressive loss of neuronal structure, progressive loss of neuronal function, or progressive neuronal cell death.

As used herein, the singular forms "a", "an" and "the" include the plural forms.

The terms "about" and "approximately" refer to approximately the same number or value as what is intended, including an acceptable degree of error in the measured quantity given the nature or accuracy of the measurement.

As used herein, the terms "about" and "approximately" are generally understood to encompass ± 20% of a specified amount, frequency, or value. Unless otherwise indicated, the numerical values set forth herein are approximate, meaning that the term "about" or "approximately" can be inferred without explicit recitation.

The terms "administration" or "administering" as used herein refer to (1) providing, administering, dosing and/or prescribing a composition of the present disclosure by or under the direction of a health care practitioner or an authorized agent thereof, and (2) administering, taking or consuming a composition of the present disclosure by a patient or himself or herself.

Reference throughout to "leucine" and "acetyl-leucine" includes pharmaceutically acceptable salts thereof, even if not explicitly stated.

Leucine or acetyl-leucine may be in racemic form, meaning that the compound contains about equal amounts of the enantiomers. Alternatively, it may be present in enantiomeric excess of the L enantiomer or the D enantiomer. Leucine or acetyl-leucine may be in the form of a single enantiomer of the L enantiomer or the D enantiomer. In one embodiment, the single enantiomeric form is the L enantiomer. Racemic and enantiomeric forms can be included according to procedures known in the art.

Reference herein to a "pharmaceutically acceptable salt" is to any salt formulation suitable for pharmaceutical use. Pharmaceutically acceptable salts include, but are not limited to: amine salts such as N, N '-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris (hydroxymethyl) aminomethane, and the like; alkali metal salts such as lithium, potassium, sodium, etc.; alkaline earth metal salts such as barium, calcium, magnesium, and the like; transition metal salts such as zinc, aluminum, and the like; other metal salts such as sodium hydrogen phosphate, disodium phosphate, and the like; inorganic acids such as hydrochloride, sulfate, and the like; organic acid salts such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate, and the like.

Leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated and administered to a subject according to teachings known in the art. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated into a pharmaceutical composition. The pharmaceutical composition may comprise leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Reference to a pharmaceutical composition encompasses the active agent (e.g. leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof) alone or in the form of a pharmaceutical composition.

The pharmaceutical composition may take any of a number of different forms, depending, inter alia, on the manner in which it is used. Thus, for example, it may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposomal suspension, or any other suitable form that can be administered to a human or animal in need of treatment.

Reference herein to a "pharmaceutically acceptable carrier" is to any known compound or combination of known compounds known to those skilled in the art that can be used to formulate a pharmaceutical composition. It will be appreciated that the carrier of the pharmaceutical composition should be one that is tolerated by the subject to whom it is administered.

In one embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or tablet. Pharmaceutically acceptable solid carriers may include, but are not limited to, one or more substances that may also act as flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet disintegrants. The carrier may also be an encapsulating material. In powders, the carrier may be a finely divided solid which is in admixture with the finely divided active agent of the invention. In tablets, the active agent may be mixed with a carrier having the necessary tabletting properties in suitable proportions and compacted in the shape and size desired. For example, powders and tablets may contain up to 99% active agent. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier may be a gel, and the composition may be in the form of a cream or the like.

The carrier may include, but is not limited to, one or more excipients or diluents. Examples of excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide and the like.

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. Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof may be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include: water (containing in part the above additives, such as cellulose derivatives, e.g., sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric 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 liquid carriers are useful in compositions for parenteral administration in the form of sterile liquids. The liquid carrier for the pressurized composition may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions as sterile solutions or suspensions may be used by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and subcutaneous injection. The active agent may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other suitable sterile injection medium.

The compositions may be administered orally in the form of sterile solutions or suspensions containing other solutes or suspending agents (e.g., sufficient saline or glucose to render the solution isotonic), bile salts, acacia, gelatin, sorbitan monooleate, polysorbate 80 (oleate of sorbitol and its anhydrides copolymerized with ethylene oxide), and the like. The compositions may also be administered orally in the form of liquid or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders, and liquid forms such as solutions, syrups, elixirs and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

The composition may alternatively 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.

Leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof may be incorporated into a slow release or delayed release device. Such devices may, for example, be inserted on or under the skin and the drug may be released over a period of weeks or even months. Such a device may be advantageous when long-term treatment with leucine or acetyl-leucine, possibly requiring frequent administration (e.g., at least daily administration), according to the present disclosure, is required.

In one embodiment, the pharmaceutical composition is a solid oral dosage form, such as a tablet. In tablets, the active agent may be mixed with a carrier having the necessary tabletting properties, for example a pharmaceutically acceptable carrier, in suitable proportions and compacted in the shape and size desired. The tablets may contain up to 99% by weight of active agent.

Pharmaceutical compositions in solid oral dosage form (e.g., tablets) may be prepared by any method known in the art of pharmacy. Pharmaceutical compositions are generally prepared by mixing the active agent with conventional pharmaceutically acceptable carriers.

The tablets may be formulated as known in the art. For exampleIncluding wheat starch, pregelatinized corn (corn) starch, calcium carbonate, and magnesium stearate as excipients. The same or similar excipients may be used with the present disclosure, for example.

700mg per tabletThe composition of the tablets was as follows: 500mg of acetyl-DL-leucine, 88mg of wheat starch, 88mg of pregelatinized corn (maize) starch, 13mg of calcium carbonate and 11mg of magnesium stearate. The same tablet may be used with the present disclosure, for example.

As described above, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions in a variety of different forms and administered. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions to facilitate its delivery across the blood-brain barrier. As another example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may be formulated into a pharmaceutical composition that bypasses the blood brain barrier. Formulations that facilitate delivery across the blood-brain barrier or that are suitable for administration in a manner that bypasses the blood-brain barrier may be used to prepare and administer leucine (non-acetylated) as described herein. As demonstrated in the present disclosure, exposure of cells exhibiting a lysosomal disease phenotype to leucine, as with exposure to acetyl-leucine, improved cell dysfunction (e.g., by reducing lysosomal storage volume to control values), demonstrating similar activity of leucine and acetyl-leucine (see fig. 14).

In one embodiment, the pharmaceutical composition (e.g., comprising leucine or a salt thereof) is formulated for nano-delivery, e.g., a colloidal drug-carrier system. Suitable examples include, but are not limited to, liposomes, nanoparticles (e.g., polymers, lipids, and inorganic nanoparticles), nanogels, dendrimers, micelles, nanoemulsions, polymersomes, vesicles,Exosomes and quantum dots. See, e.g., Patel et al, "crosslinking the Blood-Brain Barrier: Recent Advances in drug delivery to the Brain," CNS Drugs 31:109-133 (2017); kabanov et al, "New technology for Drug Delivery across the Blood Brain Barrier," Curr Pharm Des.,10(12): 1355-; cheng et al, "high Stabilized cups Nanoparticles reinforced In Vitro Blood-Brain Barrier Model and In Alzheimer's Disease Tg2576Mice," The AAPS Journal, vol.15, No.2, pp.324-336 (2013);etc. "Production of L-Leucine Nanoparticles units of vacuum Conditions Using an Aerosol Flow reactor method", "Journal of Nanomaterials, vol.2008, aryl ID 680897 (2008).

In one embodiment, the pharmaceutical composition (e.g., comprising leucine or a salt thereof) is formulated for delivery directly to the Central Nervous System (CNS), e.g., by injection or infusion. Formulations and methods for direct delivery to the CNS are known in the art. See, for example, U.S. patent 9,283,181. Examples of such administration include, but are not limited to, intranasal, intraventricular, intrathecal, intracranial, and delivery by nasal mucosal graft.

In one embodiment, the pharmaceutical composition is formulated for (and administered by) intranasal delivery. See, for example, Hanson et al, "internal delivery methods the blood-purifying barrier target thermal agents to the central nervous system and the therapeutic respiratory disease," BMC neurosci.9(Suppl 3): S5 (2008). In one embodiment, the pharmaceutical composition is formulated for delivery via (and administration through) a nasal mucosal graft. In one embodiment, the pharmaceutical composition is formulated for intraventricular injection or infusion (and administered by intraventricular injection or infusion). In another embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal intracisternal injection or infusion. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal lumbar injection or infusion. For example, the active agent may be formulated for Intrathecal administration and/or Intrathecal administration in a manner identical or similar to that discussed in Ory et al, "Intraregenerative 2-hydroxyproyl- β -cyclic depletion devices scientific research in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial," Vol.390, Issue 10104, pp.1758-1768 (2017).

Various techniques may be used, including but not limited to injection by drilling (burrhole) or puncture of the brain or waist, etc., as known in the art. Various devices, whether internal (e.g., implanted) or external, may be used for delivery as known in the art, such as pumps, catheters, reservoirs, and the like. In one embodiment, the administration interval is once every two weeks.

In one embodiment, the administration interval is monthly. In one embodiment, the administration interval is once every two months. In one embodiment, the administration interval is twice a month. In one embodiment, the administration interval is once per week. In one embodiment, the administration interval is twice or several times per week. In one embodiment, the administration interval is daily. In one embodiment, administration is continuous, e.g., continuous infusion.

Leucine or a pharmaceutically acceptable salt thereof may be administered in a dose or amount equivalent to acetyl-leucine disclosed herein and adjusted for delivery directly to the CNS or across the blood-brain barrier.

Similarly, acetyl-leucine or a pharmaceutically acceptable salt thereof may be administered in a dose or amount as disclosed herein; the dosage may be adjusted according to its route of administration (e.g., direct delivery to the CNS).

The present disclosure describes leucine, acetyl-leucine, or pharmaceutically acceptable salts thereof, including compositions and methods thereof, for treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease in a subject in need thereof. A subject in need thereof may have a genetic, biochemical, or other similar identifiable marker of a neurodegenerative disease. For example, the marker of neurodegenerative disease may be a cellular marker. A subject in need thereof can be diagnosed as having a neurodegenerative disease. For example, a subject may have been diagnosed with a neurodegenerative disease based on genetic, biochemical, or other similar identifiable markers. A subject in need thereof may be suspected of having or at risk of having a neurodegenerative disease. For example, the subject may have a genetic predisposition to a neurodegenerative disease (e.g., the subject may have one or more family members with a neurodegenerative disease). A subject in need thereof may have symptoms (i.e., have one or more symptoms associated with a neurodegenerative disease). A subject in need thereof may be asymptomatic. It should be understood that the terms "symptomatic" and "asymptomatic" are used when referring to the symptoms of a neurodegenerative disease. Subjects with a genetic, biochemical, or other similarly identifiable marker of a neurodegenerative disease, e.g., subjects diagnosed as having a neurodegenerative disease without further symptoms of the disorder based on a genetic, biochemical, or other similarly identifiable marker, are included within the scope of "asymptomatic" for purposes of this disclosure.

As used herein, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" and the like refers to delaying the onset of one or more symptoms of a neurodegenerative disease or neurodegenerative disease that would otherwise be expected to manifest as typical disease progression, reducing the severity of a neurodegenerative disease or reducing the severity of one or more existing symptoms associated with a neurodegenerative disease or eliminating one or more existing symptoms associated with a neurodegenerative disease, delaying the progression of one or more symptoms of a neurodegenerative disease or neurodegenerative disease over time as compared to typical disease progression, and/or reversing the progression of one or more symptoms of a neurodegenerative disease or neurodegenerative disease over time. "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" may also refer to improving a biochemical marker of a neurodegenerative disease.

As used herein, "classical disease progression," "disease progression that would normally be expected," and the like, refer to 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, for example, on a known scale, index, rating or score, or other suitable test, for assessing progression of a neurodegenerative disease, one or more symptoms of a neurodegenerative disease, or a biochemical marker of a neurodegenerative disease, such as those described herein as examples. The scale, index, rating, score, or other suitable test may correspond to the overall progression of the disease or the progression of one or more symptoms associated with the disease. For example, a typical or expected disease progression may be based on a typical or expected onset or severity of a neurodegenerative disease or a symptom or set of symptoms associated with a neurodegenerative disease. Typical or expected disease progression may be determined subject-by-subject, or may be determined based on what is commonly observed or experienced with a collection of subjects (e.g., a population or subpopulation of subjects) affected by a neurodegenerative disease. The subpopulations may include, for example, subpopulations of the same gender, subpopulations of the same or similar age, subpopulations having the same or similar timing of onset of one or more symptoms, and the like.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to delaying the onset of one or more symptoms of a neurodegenerative disease or neurodegenerative disease (which disease or symptoms would otherwise be expected to manifest as typical disease progression). As used herein, "delaying the onset of, or preventing the onset of, one or more symptoms of a neurodegenerative disease or neurodegenerative disease" or the like refers to increasing the time before, or preventing the onset of, one or more symptoms of a neurodegenerative disease or neurodegenerative disease. For example, an episode may be said to be delayed when the time before manifestation of the neurodegenerative disease or one or more symptoms of the neurodegenerative disease is at least 5% longer than the time observed according to typical disease progression. Further, for example, an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% is observed. In one embodiment, the subject is asymptomatic. Administration of leucine or acetyl-leucine can be initiated at the time of asymptomatic subject to delay onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease (which would otherwise be expected to manifest as typical disease progression). In another embodiment, the subject has symptoms. Administration of leucine or acetyl-leucine can be initiated when a subject has some symptoms that would otherwise be expected to manifest in accordance with typical disease progression, to delay the onset of one or more other symptoms of a neurodegenerative disease. The subject in need thereof may continue to receive leucine or acetyl-leucine treatment according to the duration described herein. In one embodiment, the treatment prevents the onset of one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest as typical disease progression.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to reducing the severity of a neurodegenerative disease, or reducing the severity of or eliminating one or more existing symptoms associated with a neurodegenerative disease. The assessment of the severity of a neurodegenerative disease or an existing symptom may utilize known scales, indices, ratings or scores, such as those described herein as examples, or other suitable tests for assessing severity. For example, a scale, index, rating, score, or other suitable test may correspond to the overall severity of a disease or the severity of one or more symptoms associated with a disease. In one embodiment, the treatment improves such assessment from a characteristic value or degree for a symptomatic patient to a characteristic value or degree for a non-symptomatic patient.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to delaying the progression of the neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease over time, or reversing the progression of the neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease over time, as compared to the progression of a typical disease. The time at which treatment is delayed or reversed in progression may be consistent with the duration of treatment described herein. Treatment may continue, for example, for a delay or reversal of progression of 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. Treatment may continue to delay or reverse 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 delay or reverse progression for a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. Treatment may delay or reverse the progression of the neurodegenerative disease or one or more symptoms associated with the neurodegenerative disease within the life of the patient.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to delaying the progression of one or more symptoms of a neurodegenerative disease or neurodegenerative disease over time as compared to the progression of a typical disease. As used herein, "delaying the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time" and the like refers to slowing and/or stopping the progression of a disease or one or more symptoms of a disease over time (e.g., slowing and/or stopping the worsening or increasing severity of a disease or one or more symptoms of a disease). Determination of disease progression may, for example, utilize known scales, indices, ratings or scores, such as those described herein as examples, or other suitable tests for assessing progression. For example, a scale, index, rating, score, or other suitable test may correspond to the overall progression of a disease, or to the progression of one or more symptoms associated with a disease. In one embodiment, "delaying the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to a subject's disease severity value (e.g., the overall severity or the severity of one or more symptoms) that is not meaningfully increased (e.g., remains at least substantially unchanged) as determined by a scale, index, rating, score, or the like, or other suitable test for assessing severity. In one embodiment, "delaying the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to preventing a subject from reaching a severity value, or increasing the time for a subject to reach a severity value (e.g., decreasing the rate of change of increase in severity), as determined according to a known scale, index, rating, score, etc., or other suitable test for assessing progression, as compared to a value corresponding to typical disease progression. For example, progression may be said to be delayed when the time to reach a severity value is at least 5% longer than the time observed according to typical disease progression. As another 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. The time at which progression of the neurodegenerative disease or one or more symptoms of the neurodegenerative disease is delayed by the treatment may be consistent with the duration of treatment described herein. In one embodiment, the treatment delays progression for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. Treatment may delay 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. Treatment may delay progression throughout the life of the patient.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to reversing the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease over time. As used herein, "reversing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease over time" or the like refers to stopping the progression of the disease or one or more symptoms of the disease and reducing the severity of the disease or one or more symptoms of the disease over time. The determination of disease progression and severity can be made, for example, using known scales, indices, ratings or scores, such as those described herein as examples, or using other suitable tests for assessing progression and severity. For example, a scale, index, rating, score, or other suitable test may correspond to the overall progression and severity of a disease, or to the progression and severity of one or more symptoms associated with a disease. In one embodiment, "reversing the progression of neurodegenerative disease or one or more symptoms of neurodegenerative disease over time" refers to the subject's disease severity value (e.g., overall severity or severity of one or more symptoms) improving over time (i.e., showing a decrease in severity over time) as determined by a known scale, index, rating, score, or the like, or other suitable test for assessing severity. The duration of treatment to reverse the progression of the neurodegenerative disease or one or more symptoms of the neurodegenerative disease may be consistent with the duration of treatment described herein. In one embodiment, 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 yet another embodiment, the treatment reversal progression is 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. Treatment can reverse progression throughout the life of the patient.

In one embodiment, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" refers to improving a biochemical marker of a neurodegenerative disease in a subject (e.g., increased levels of stored metabolites, or secondary biochemical changes resulting from primary storage). Biochemical markers are signals of disease activity and can provide a persistent indication of disease severity and progression over time. In one embodiment, the biochemical marker is improved relative to a control value. In one embodiment, the biochemical marker is selected from: increased lysosomal volume, increased levels of Glycosphingolipids (GSLs), increased levels of microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II), and increased levels of the C-terminal fragment of amyloid precursor protein (APP-CTF). In one embodiment, the biochemical marker is increased lysosomal volume, and the treatment decreases lysosomal volume in the subject. In one embodiment, the biochemical marker is increased Glycosphingolipid (GSL) levels, and the treatment decreases GSL levels in the subject. In one embodiment, the biochemical marker is increased level of microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) and the treatment decreases level of LC3-II in the subject. In one embodiment, the biochemical marker is increased levels of the C-terminal fragment of amyloid precursor protein (APP-CTF), and the treatment decreases levels of APP-CTF in the subject. In one embodiment, the treatment improves the biochemical marker over time. For example, in one embodiment, improving a biochemical marker over time means that treatment improves the biochemical marker towards a control value over time, prevents the progression of the biochemical marker over time, and/or delays the progression of the biochemical marker over time as compared to typical disease progression. The time for the treatment to improve the biochemical marker may be consistent with the duration of treatment described herein. In one embodiment, the treatment improves the biochemical marker for at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. The treatment may improve the biochemical marker for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. Treatment may improve biochemical markers throughout the life of the patient.

"symptoms" of a neurodegenerative disease include any clinical or laboratory manifestation associated with the neurodegenerative disease and are not limited to what a subject can feel or observe. Symptoms described herein include, but are not limited to, neurological and psychiatric symptoms. Examples of neurological symptoms include ataxia, other movement disorders such as hypokinesia, rigidity, tremor or dystonia, Restless Leg Syndrome (RLS), central eye movement disorders such as vertical and horizontal supranuclear saccadic/staring palsy, and neuropsychological deficits such as dementia. In one embodiment, the neurological condition is RLS. In one embodiment, treating a neurodegenerative disease as described herein comprises treating RLS in a subject, e.g., reducing the severity or ameliorating RLS, delaying or inhibiting the progression of RLS, or eliminating RLS. Examples of psychiatric symptoms include depression, behavioral disorders, or psychosis. The onset of symptoms may range from birth to adulthood.

The progression of neurodegenerative disease over time or under treatment can be monitored, for example, using one or more known tests at two or more time points and comparing the results. Disease progression and/or severity can be assessed, for example, using the ataxia rating Scale (SARA), the spinocerebellar ataxia function index (SCAFI), the International Council Ataxia Rating Scale (ICARS), the simple ataxia rating scale (BARS), the modified disability rating scale (mDRS), the EuroQol 5Q-5D-5L (EQ-5D-5L), the Visual Analog Scale (VAS), neuropsychological tests, such as the Wechsler adult mental Scale revision (WAIS-R), the Wechsler mental Scale Children-IV (WISC-IV), the Montreal cognitive assessment (MoCA), and scales used in dyskinesias, such as the Unified Parkinson Rating Scale (UPRS) or the Unified Multiple System Atrophy Rating Scale (UMSARS), or other suitable tests. For certain LSDs, such as NPC, specific scores such as Clinical Severity Score (CSS) and Annual Severity Increment Score (ASIS) (see Yanjanin et al, "Linear clinical progress, Independent of Age of Onset, in Niemann-Pick Disease, Type C," Am JMed Genet Part B153B: 132-. For example, the severity of NPC patients can be quantified by assigning CSS, which evaluates various parameters of the disease (bed-escape activity, seizures, eye movements, etc.) and gives a score of 5 points per parameter. A higher score equates to a more severe degree. ASIS quantifies the annual rate of change of CSS, which is calculated by dividing CSS by patient age. In this regard, some of these tests are characteristic of symptomatic neurodegenerative disease patients and the clear progression and/or severity of the disease.

Thus, "treating a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" can be equivalent, for example, to achieving an improved assessment result, 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 other tests suitable 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 existing symptoms of a neurodegenerative disease or these existing symptoms" means improving the SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA score, or the results of other suitable tests for assessing severity, e.g., improving the score or results from a characteristic severity value for a symptomatic subject to a characteristic value for a non-symptomatic subject. In another embodiment, "delaying the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease" means that the subject has no meaningful increase (e.g., remains at least substantially unchanged) in the results of the SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA scores or other suitable tests for assessing progression. In yet another embodiment, "delaying the progression of neurodegenerative disease or one or more symptoms associated with neurodegenerative disease" means preventing the results of the subject's SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA scores, or other suitable tests for assessing progression, from reaching a value comparable to, or increasing the time taken to reach, a typical disease progression. In another embodiment, "reversing the progression of neurodegenerative disease or one or more symptoms of neurodegenerative disease over time" means that the subject's SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, and/or MoCA score, or other suitable test for assessing progression, improves over time (i.e., shows a decrease in severity over time).

For example, to assess overall neurological status, mDRS, a four-domain scale (bed-exit activity, steering, speech, and swallowing) can be applied. Cerebellar function can be assessed using SARA, an eight item clinical rating scale (gait, stance, sitting, language, fine motor function and tropism; range 0-40, where 0 is the best neurological state and 40 is the worst), and SCAFI, which includes 8 meters walking time (8 MW; the patient is asked to walk as quickly as possible from one line to another twice, not including turns), 9-hole spile test (9HPT), and "PATA" repeats within 10 seconds. Subjective impairment and quality of life can be assessed using the EQ-5D-5L questionnaire and VAS. To assess eye movement function, three-dimensional video ophthalmograms (EyeSeeCam) may be used to measure peak velocity of saccades, gain for smooth pursuits, peak slow phase velocity of fixation-induced nystagmus (gaze-preserving function), peak slow phase velocity of visual power nystagmus, and horizontal vestibulo-ocular reflex gain. To assess cognitive status, different areas of cognition, including attention and concentration, executive function, memory, language, visual structural skills, conceptual thinking, computation and orientation, may be assessed using WAIS-R or WISC-IV and MoCA, up to 30 points and 26 points as a threshold score. The skilled person will know how to perform these tests and other such tests.

Restless Leg Syndrome (RLS) is a neurological disorder characterized by overwhelming impulses that move the body, usually at rest with uncomfortable or strange sensations. It most commonly affects the leg, particularly between the knee and the ankle, but may also affect other areas such as the arm, torso or even phantom limbs. In one embodiment of the disclosure, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof is used in a method of treating RLS in a subject suffering from a neurodegenerative disease. The method comprises administering to the subject a therapeutically effective amount of leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof. In one embodiment, a subject with RLS has a neurodegenerative disease selected from parkinsonism (e.g., as described herein), spinocerebellar ataxia, huntington's disease, hereditary spastic paraparesis, Amyotrophic Lateral Sclerosis (ALS), and alzheimer's disease. In one embodiment, the neurodegenerative disease is selected from frontotemporal dementia, dementia with lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. In one embodiment, the neurodegenerative disease is a motor neuron disease (e.g., as described herein). In one embodiment, the neurodegenerative disease is parkinson's disease. In one embodiment, the neurodegenerative disease is associated with dysfunction of the dopaminergic system (e.g., loss of dopaminergic cells). In one embodiment, RLS is a symptom of, or may be associated with, a neurodegenerative disease. In another embodiment of the disclosure, when the RLS is characterized by a neurodegenerative disease, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, is used to treat RLS in a subject in need thereof.

Treating RLS as discussed herein may include reducing the severity of RLS or reducing, inhibiting, or eliminating one or more symptoms of RLS. "symptoms" of RLS include any clinical or laboratory manifestations associated with RLS. The symptoms of RLS are typically, but not necessarily, manifestations that can be felt or observed by the subject associated with the disease. Symptoms associated with RLS include, but are not limited to, blunted calf sensation, periodic leg movements in sleep (PLMS), unpleasant leg sensations, motor impulses, hyperactivity, sleep disturbances, excessive daytime sleepiness, and the like. In one embodiment, the RLS-related symptoms that are reduced, inhibited or eliminated are selected from any one or combination of lower leg sensory dullness, periodic leg movements in sleep (PLMS), unpleasant leg sensations, motor impulses, hyperactivity, excessive daytime sleepiness and sleep disturbances.

The severity of RLS or one or more symptoms of RLS can be assessed, for example, using a known scale, index, rating, or score. For example, a scale, index, rating, score, or other suitable test may correspond to the overall severity of RLS or the severity of one or more symptoms associated with RLS. In one embodiment, the treatment described herein improves the outcome of such assessment from a characteristic value or degree in a symptomatic subject to a characteristic value or degree in a non-symptomatic subject. In one embodiment, the treatment described herein improves the outcome of such assessment compared to baseline. The baseline can be, for example, the condition of the subject prior to initiating any treatment for RLS or prior to initiating treatment for RLS with leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof. Alternatively, the baseline may be, for example, the condition of the subject after a certain time of treatment for RLS.

An extensively reported rating scale was developed by the International Restless leg Syndrome research Group (IRLSSG) (http:// www.irlssg.org /), known as the International Restless leg Syndrome research Group rating Scale "(IRLS) (Walters et al, Validation of the International resource management sheets for the resource management documents 2003Apr 01; 4(2): 121-32). IRLS is a 10-term scale with a score ranging from 0 (asymptomatic) to 40. Scores >30 were considered very severe, severe (scores 21-30), moderate (scores 11-20), and ≦ 10 mild. The use of this scale is common for clinical assessment, research and therapeutic trials of RLS. In one embodiment, treatment with leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof as described herein reduces the international restless leg syndrome study group rating scale (IRLS) of the subject compared to baseline. In one embodiment, the IRLS is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% compared to baseline. In one embodiment, the IRLS is reduced by at least 60%, at least 70%, at least 80%, at least 90% or 100%. .

In one embodiment, acetyl-leucine or a pharmaceutically acceptable salt thereof may be administered in a dose of, for example, from about 500mg to about 15 g/day or from about 500mg to about 10 g/day, for example from about 1.5g to about 10 g/day, optionally by solid or liquid oral route. The dosage of administration of acetyl-leucine or a pharmaceutically acceptable salt thereof may, for example, be referred toThe dosage of (a) is 1.5g to 2 g/day for an adult, 3-4 tablets, two doses in the morning and evening.

If one enantiomer is administered, the dosage may be reduced accordingly. For example, if only acetyl-L-leucine or only acetyl-D-leucine is administered, the dose may be from about 250mg to about 15 g/day, from about 250mg to about 10 g/day, or from about 250mg to about 5 g/day, e.g., from about 0.75g to about 5 g/day.

In one embodiment, a dose of about 1g to about 15 g/day, about 1g to about 10 g/day, or about 1.5g to about 7 g/day is administered. It can be from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14g to about 15 g/day. It can be from about 2, 3, 4, 5, 6, 7, 8, or 9g to about 10 g/day. It may be more than about 1.5 g/day, but less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 g/day. In one embodiment, the dose is from about 4g to about 6 g/day. In one embodiment, the dose is from about 4g to about 5 g/day. In one embodiment, the dose is about 4.5 g/day. In one embodiment, the dose is about 5 g/day. In one embodiment, these doses are administered in solid oral dosage forms, particularly tablets. In another embodiment, these doses are for acetyl-leucine when in racemic form. When enantiomeric excess is present, the dosage of acetyl-leucine can be lower than those described herein, e.g., about 50% lower. Thus, the present disclosure also expressly encompasses dosage ranges as described above when halved.

In one embodiment, the total daily dose may be dispersed over multiple administrations, i.e. the administrations may be carried out two or more times per day to reach the total daily dose. For example, the number of tablets required to provide a total daily dose of acetyl-leucine may be divided into two administrations (e.g., morning and evening) or three administrations (e.g., morning, noon and evening). Each administration may be administered with or without food as appropriate. For example, acetyl-leucine may be administered about 1 or about 2 hours before a meal, e.g., at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about 1 hour before a meal, or may be administered about 1, about 2, or about 3 hours after a meal, e.g., waiting at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours after a meal. For example, a total daily dose of 4.5 grams of acetyl-DL-leucine may be taken as 3 tablets before, during or after breakfast(or equivalent), another 3 tablets before, during or after lunch and another 3 tablets before, during or after dinner.

Administration of leucine or acetyl-leucine of the present disclosure may begin before or after a subject is found to have a genetically, biochemically, or other similarly identifiable marker of a neurodegenerative disease, e.g., in the former case, when the subject is suspected of having or at risk of having a neurodegenerative disease. The administration may be initiated at or near the time the subject is found to have a genetic, biochemical or other similar identifiable marker of a neurodegenerative disease. Similarly, administration may begin before, at or near, or after the subject is diagnosed with the neurodegenerative disease, for example before, at or near, or after the subject is found to have a genetic, biochemical, or other similar identifiable marker of the neurodegenerative disease. Leucine or acetyl-leucine may be administered initially when the subject is symptomatic or asymptomatic. In particular, one of the advantages of treatment with leucine or acetyl-leucine according to the present disclosure is that administration may begin as early as immediately after a subject is found to have a genetic and/or biochemical marker of a neurodegenerative disease, but before the subject exhibits symptoms of the neurodegenerative disease (as opposed to the genetic and/or biochemical marker, i.e., the subject is asymptomatic), or before the subject exhibits one or more symptoms that are considered characteristic of the disease. The treatment may delay the onset of the neurodegenerative disease or one or more symptoms associated with the neurodegenerative disease, as described herein. The treatment may also be for the duration described herein.

As discussed herein, an advantage of treatment with leucine or acetyl-leucine according to the present disclosure is that it can be administered for a long time, thereby delaying or even reversing the progression of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease in a subject, e.g., as compared to typical disease progression. The duration of treatment may be, for example, about 7 days or longer, about 2 weeks or longer, about 3 weeks or longer, about 1 month or longer, about 6 weeks or longer, about 7 weeks or longer, or about 2 months or longer. In one embodiment, it is about 3 months or longer, about 4 months or longer, about 5 months or longer, or about 6 months or longer. The duration of treatment may be about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The duration of treatment may be the life span of the patient.

Any and all combinations of dosage forms, dosages, regimens, and treatment durations are contemplated and encompassed by the present invention. In one embodiment, the dose is from about 4g to about 10 g/day administered 1, 2 or 3 times per day for a treatment duration of about 2 months or more. In another embodiment, the dose is greater than 4 grams but not greater than 5 grams per day administered 1, 2, or 3 times per day for a treatment duration of about 6 months or more. The dosage form may be a solid oral dosage form, in particular a tablet.

The pharmaceutical compositions described herein can be used as a monotherapy (e.g., using only the active agent) to treat a neurodegenerative disease in a subject. Alternatively, the pharmaceutical composition may be used as an adjunct to or in combination with other known therapies, e.g., for treating a neurodegenerative disease in a subject.

Neurodegenerative diseases can, but need not, be associated with lysosomal dysfunction (e.g., lysosomal storage defects). Neurodegenerative diseases of the present disclosure that are not associated with lysosomal dysfunction include, but are not limited to: restless Leg Syndrome (RLS), Alexandritic disease, Alper's disease, cerebral palsy, Kekahn's syndrome, corticobasal degeneration, HIV-related dementia, Kennedy's disease, neuroleptospirosis, primary lateral sclerosis of the spinal cord, Leffermonian's disease, Sheer's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, hereditary motor and sensory neuropathy with proximal dominance, Hedgehog wobble syndrome (WHS), progressive muscular atrophy (Duchenne-Aran muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-related neurocognitive disorder (HAND), vascular Parkinson's syndrome, lower-half-body Parkinson's syndrome, lower-cerebellar tremor, and cerebellar ataxia, including spinocerebellar ataxia (SCA)4, spinocerebellar ataxia (SCA)5(Lincoln ataxia), Spinocerebellar ataxia (SCA)8, spinocerebellar ataxia (SCA)10, spinocerebellar ataxia (SCA)11, spinocerebellar ataxia (SCA)12, 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)23, spinocerebellar ataxia (SCA)25, spinocerebellar ataxia (SCA)26, spinocerebellar ataxia (SCA)27, spinocerebellar ataxia (SCA)29, spinocerebellar ataxia (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, Episodic Ataxia (EA)6, Episodic Ataxia (EA)7, spinocerebellar ataxia (SCA)28, spinocerebellar ataxia (SCA)24 (spinocerebellar ataxia autosomal recessive syndrome of type 4 (SCAR 4)), spinocerebellar ataxia with invasion (saccade) (AOA1), spinocerebellar ataxia of type 1 (SCA 1), ataxia of type 2 (AAC) 2), ataxia of type 4 (AOA) with ataxia), Spinocerebellar ataxia type 10 autosomal recessive syndrome (SCAR 10), mitochondrial recessive ataxia syndrome (MIRAS), myoclonic epilepsy, myopathic sensory ataxia (MEMSA), dysarthric ophthalmoplegia of Sensory Ataxia Neuropathy (SANDO), infantile-onset spinocerebellar ataxia, hereditary spastic paraplegia 7(HSP SPG7 gene), mitochondrial myopathic encephalopathy lactic acidosis stroke syndrome (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), neurogenic myasthenia-asthenia and retinitis pigmentosa (FXNARP), Kearns-Sayre (KSS), fragile X tremor/ataxia syndrome (TAS), Arts syndrome, X-linked spinocerebellar ataxia 1, X-linked spinocerebellar ataxia 2, X-linked spinocerebellar ataxia 3, X-linked spinocerebellar ataxia 4 or X-linked cerebellar ataxia 5 (FXS 3), Christianson type X-linked syndrome with mental retardation, X-linked siderobic anemia, idiopathic late-onset cerebellar ataxia, sporadic adult-onset ataxia of unknown etiology (SAOA), and cerebellar ataxia neuropathy vestibular nonreflective syndrome (CANVAS). In one embodiment, the neurodegenerative disease not associated with lysosomal dysfunction is corticobasal degeneration, SCA28, and AOA 4.

As noted above, many neurodegenerative diseases are associated with lysosomal dysfunction, including neurodegenerative Lysosomal Storage Diseases (LSDs) and many other neurodegenerative diseases that have been proposed to be associated with lysosomal defects. 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-; 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).

In one embodiment, the neurodegenerative disease is associated with a lysosomal dysfunction (e.g., a lysosomal storage defect). Neurodegenerative diseases of the present disclosure 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, sle-au-o syndrome (SLOS) (congenital error in cholesterol synthesis), dangill disease, paget's disease, pick's disease, frontotemporal lobar dementia parkinsonism linked to chromosome 17, prion diseases including: scrapie, transmissible mink encephalopathy, chronic wasting disease, Bovine Spongiform Encephalopathy (BSE), feline spongiform encephalopathy, exotic ungulate encephalopathy, kuru, Creutzfeldt-Jakob disease, Gerstmann--Scheinker syndrome and fatal familial insomnia, progressive supranuclear palsy, spinal muscular atrophy, neurodegenerative LSD and cerebellar ataxia including spinocerebellar ataxia (SCA)1, spinocerebellar ataxia (SCA)2, spinocerebellar ataxia (SCA)3 (equine-johnson disease), spinocerebellar ataxia (SCA)6, spinocerebellar ataxia (SCA)7, spinocerebellar ataxia (SCA)17, dentatorubral pallidoluysian atrophy, schelerian hypothalamic atrophyAutosomal recessive spastic ataxia of the type Wagner-Sagner (ARSACS), autosomal recessive cerebellar ataxia type 1 (Beauce-type Recessive Ataxia (RAB), SYNE-1 mutation), autosomal recessive cerebellar ataxia type 2 (spinocerebellar ataxia autosomal recessive 9, SCAR9), ataxia with vitamin E deficiency (AVED), ataxia telangiectasia (Louisbara disease), Friedreich ataxia (FRDA) and ataxia with coenzyme Q10 deficiency. In one embodiment, the neurodegenerative disease associated with lysosomal dysfunction is selected from the group consisting of 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, sjogren-olsyndrome (SLOS) (congenital error in cholesterol synthesis), dangill disease, peimeri's disease, pick's disease, frontotemporal lobar dementia with parkinsonism, prion disease, progressive supranuclear palsy, and spinal muscular atrophy. In one embodiment, the neurodegenerative disease associated with lysosomal dysfunction is selected from the group consisting of ALS, MSA-P, MSA-C, frontotemporal dementia with parkinsonism, progressive supranuclear palsy, SCA28, SCA 1 and alzheimer's disease.

Neurodegenerative LSDs are characterized by the accumulation of undigested or partially digested macromolecules, which cause cellular dysfunction and neurodegeneration, which is often progressive, leading to physical disability and/or mental deterioration. These conditions often occur in the first few years of life and serious advances have led to frequent hospitalizations. Patients often die by the age of ten if left untreated. Adult onset patients are also described. Neurodegenerative LSDs described in this disclosure include, but are not limited to: neuronal ceroid lipofuscinosis (types 1-10), gaucher 'S disease type 2/3 (neurogenic), Krabbe' S disease, multiple sulfatase deficiencies, 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, Thalasi-saxosis, Sandhoff disease, Fabry disease, galactosialidosis storage disease, MPS, Fabry disease, Ocylor disease, GM1 gangliosidosis, MPS variant GM2 gangliosidosis, Metachromatic Leukodystrophy (MLD), mucopolysaccharidosis including IHS, IS, MPS-S, mannosidosis, mannosida, IIIb, MPS, IHc, IHVII, and beta-glycoside storage disease, Aspartylaminoglucamine diabetes, fucose storage disease, Salla disease, infant free sialic acid storage disease (ISSD), and Danon disease. In one embodiment, the neurodegenerative LSD is selected from NPC, NPA, mucolipidosis type II, MPS IIIB, aspartylglucosaminuria, mucolipidosis type IIIA, MPS VII, Sandhoff disease, tay-saxose disease, AB variant of tay-saxose disease, and GM1 gangliosidosis. In one embodiment, the neurodegenerative disease is not selected from neurodegenerative LSDs.

In one embodiment, the neurodegenerative disease is a motor neuron disease. In one embodiment, the motor neuron disease is selected from the group consisting of 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, peimer's disease, and spinal muscular atrophy.

As noted above, in one embodiment of the present disclosure, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, is used to treat Restless Leg Syndrome (RLS) in a subject suffering from a motor neuron disease, including but not limited to any motor neuron disease described herein.

In one embodiment, the neurodegenerative disease is cerebellar ataxia. In one embodiment, the neurodegenerative disease is niemann-pick disease. In one embodiment, the neurodegenerative disease is niemann-pick disease type C. In one embodiment, the neurodegenerative disease is niemann-pick disease type a. In one embodiment, the neurodegenerative disease is parkinson's syndrome. In one embodiment, the neurodegenerative disease is neurogenic gaucher disease. In one embodiment, the neurodegenerative disease is tay-saxophone. In one embodiment, the neurodegenerative disease is Sandhoff disease. In one embodiment, the neurodegenerative disease is fabry disease. In one embodiment, the neurodegenerative disease is GM1 gangliosidosis. In one embodiment, the neurodegenerative disease is Louis-Barr syndrome. In one embodiment, the neurodegenerative disease is alzheimer's disease. In one embodiment, the neurodegenerative disease is parkinson's disease. In one embodiment, the neurodegenerative disease is multiple system atrophy. In one embodiment, the neurodegenerative disease is multiple system atrophy type C (MSA-C). In one embodiment, the neurodegenerative disease is multiple system atrophy type P (MSA-P). In one embodiment, the neurodegenerative disease is frontotemporal dementia. In one embodiment, the neurodegenerative disease is frontotemporal dementia with parkinsonism. In one embodiment, the neurodegenerative disease is lower body parkinson's syndrome. In one embodiment, the neurodegenerative disease is Amyotrophic Lateral Sclerosis (ALS). In one embodiment, the neurodegenerative disease is corticobasal degeneration syndrome. In one embodiment, the neurodegenerative disease is progressive supranuclear palsy. In one embodiment, the neurodegenerative disease is cerebellar nystagmus. In one embodiment, the neurodegenerative disease is SCA 28. In one embodiment, the neurodegenerative disease is ataxia telangiectasia. In one embodiment, the neurodegenerative disease is SCA 1. In one embodiment, the neurodegenerative disease is AOA 4.

The main symptoms of Parkinson's Disease (PD) include stiffness, tremor and slow movement. Other diseases are common to these symptoms. These diseases and PD itself are a generic term for parkinsonism. PD may be referred to as primary parkinsonism. Other examples of parkinsonism include: multiple system atrophy; progressive supranuclear palsy; normal pressure hydrocephalus; and vascular or arteriosclerotic parkinsonism. Those diseases that can be classified as parkinsonism but not PD may also be referred to as "parkinsonism-Plus syndrome". Unlike PD patients, individuals with parkinsonian-plus syndrome do not respond to levodopa. The term "parkinsonism" as used herein may refer to motor syndrome, the main symptoms of which are tremor at rest, stiffness, slowed movement and postural instability. Parkinsonism can be divided into four subtypes according to their origin: primary or idiopathic; secondary or acquired; hereditary parkinsonism; and parkinsonism plus syndrome or multiple system degeneration.

In one embodiment, the parkinsonism is a parkinsonism plus syndrome or multiple system degeneration.

In one embodiment, the parkinsonism is vascular (arteriosclerosis) parkinsonism, lower body parkinsonism, multiple system atrophy with parkinsonism predominating (MSA-P), multiple system atrophy with cerebellar features (MSA-C; sporadic olivopontine cerebellar atrophy (OPCA)), Shy-Drager syndrome, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), Lewy body dementia, pick's disease, or frontotemporal dementia parkinsonism linked to chromosome 17.

As noted above, in one embodiment of the present disclosure, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, is used to treat Restless Leg Syndrome (RLS) in a subject suffering from parkinsonism, including but not limited to any parkinsonism described herein.

Niemann-pick disease is a heterogeneous group of autosomal recessive LSDs. Common cellular features include abnormal Sphingomyelin (SM) storage in mononuclear phagocytes and parenchymal tissues, and (liver) splenomegaly. Among the three main subgroups of niemann-pick disease (a-C), NPC (previously classified as NPC and NPD, now considered to be the same disease) is classified as fatal cerebrospinal sympathetic nervous system LSD caused by unesterified cholesterol accumulation induced by abnormal intracellular cholesterol transport in the late endosomal/lysosomal compartment. Outside the CNS, the cellular characteristics of NPC include abnormal accumulation of unesterified cholesterol and other lipids (e.g., GSL) in the late endosomal/lysosomal compartment. In contrast, there is no net increase in cholesterol in the CNS (although it does have an altered profile), but there are highly elevated levels of GSL. Progressive neurodegeneration is characterized in particular by the sequential degeneration of gabaergic Purkinje neurons in the cerebellum, which is parallel to the onset and development of cerebellar symbiotic disorders and other aspects of neurological dysfunction that arise during NPC. Genetic studies have shown that NPC disease is caused by mutations in the NPC1 or NPC2 genes. The precise mechanistic link between these two genes is still unknown, and the functional roles of these proteins remain mysterious. NPC1 encodes a late endosomal/lysosomal restricted membrane multi-membrane spanning protein, while NPC2 is a lysosomal soluble cholesterol-binding protein. Sphingosine is the first lipid stored when NPC1 is inactivated, suggesting that NPC1 plays a role in transporting sphingosine from lysosomes, where sphingosine is normally produced as part of sphingolipid catabolism. The elevated sphingosine in turn leads to defects in calcium entry into the acidic reservoir, resulting in a greatly reduced calcium release from the compartment. This subsequently prevents late endosomal-lysosomal fusion (calcium-dependent process) and leads to secondary accumulation of lipids (cholesterol, sphingomyelin and glycosphingolipid), which are cargo transported by the late endocytic pathway. Other secondary consequences of inhibition of NPC1 function include defective endocytosis and failure to clear autophagic vacuoles. The NPC1/NPC2 cellular pathway has been shown to be targeted by pathogenic mycobacteria to promote their survival in late endosomes.

The NPC mouse model shares many of the same pathological features as, for example, Alzheimer's Disease (AD). It has previously been reported that microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels are elevated in NPC mice. LC3-II is a marker of autophagosome formation, and an increase in LC3-II levels may reflect impaired clearance of autophagic vesicles. Autophagosomes formed but were not cleared. Autophagy is impaired in AD and AD brain shows elevated levels of LC 3-II. Furthermore, Amyloid Precursor Protein (APP) is a precursor molecule that proteolytically produces beta amyloid (a β). A β plaques are characteristic of AD brain and have been proposed to be causative in disease pathology. The amyloid precursor protein C-terminal fragment (APP-CTF) is an intermediate in the proteolysis of APP to a β, which accumulates in the AD brain and also gradually accumulates in the brain of NPC1 mice.

Tay-saxophone disease is a fatal inherited disease of lipid metabolism characterized particularly by CNS tissues, caused by the a isozyme lacking β -hexosaminidase. Mutations in the HEXA gene encoding the alpha subunit of β -hexosaminidase result in A isozyme deficiency. Tay-saxophone is the prototype of a group of conditions GM2 gangliosidosis, characterized by GM2 gangliosidosis degradation deficiency. GM2 ganglioside (monosialoganglioside 2) has already begun to accumulate in neurons during fetal life.

Sandhoff disease is caused by a deficiency of the A and B (basic) isozymes of β -hexosaminidase. Mutations in the HEXB gene encoding the β subunit of β -hexosaminidase result in B isozyme deficiency.

GM1 gangliosidosis is caused by a β -galactosidase deficiency, which leads to lysosomal storage of GM1 ganglioside (monosialylated ganglioside 1).

Fabry disease is caused by a deficiency in α -galactosidase, which results in lysosomal storage of ceramide trihexoside.

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 disease type C. In one embodiment, the neurodegenerative disease is not cerebellar ataxia or niemann-pick disease (e.g., niemann-pick disease type C).

In one embodiment, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats weight loss, gait exacerbation, and/or motor function exacerbation associated with niemann-pick disease (e.g., niemann-pick disease type C or a) or type II mucolipidosis. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, can delay the onset, reduce the severity, or eliminate the progression of weight loss, worsening gait, and/or worsening motor function associated with niemann-pick disease (e.g., niemann-pick disease type C or a) or type II mucolipidosis, or delay or reverse the progression thereof. In one embodiment, weight loss, gait deterioration and/or motor function deterioration is associated with niemann pick disease type a or mucolipidosis type II.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats gait exacerbation, motor function exacerbation and/or reduced motility associated with Sandhoff disease. For example, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof may delay the onset, reduce the severity or eliminate, or delay or reverse the progression of gait exacerbations, motor function exacerbations and/or motor decline associated with Sandhoff disease.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats decreased coordination, tremor, decreased motility, cognitive impairment, and/or gait deterioration associated with tay-saxophone. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay the onset, reduce the severity, or eliminate the progression of decreased coordination, tremor, decreased motility, cognitive impairment, and/or worsening gait associated with tay-saxophone, or delay or reverse the progression of tay-saxophone.

In one embodiment, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats language deterioration (e.g., language fluency and/or speech regulation), gait exacerbation, reduced motility, reduced swallowing function, and/or paresis associated with Amyotrophic Lateral Sclerosis (ALS). For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, can delay the onset, reduce the severity, or eliminate the deterioration of speech (e.g., speech fluency and/or speech regulation), gait exacerbation, reduced motility, reduced swallowing function, and/or paresis associated with ALS, or delay or reverse its progression. In another embodiment, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, treats the sleep quality reduction associated with ALS. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay the onset, reduce the severity, or eliminate the sleep quality decline associated with ALS, or delay or reverse its progression.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats language deterioration, gait exacerbation and/or increased fall propensity associated with multisystemic wilting brain type (MSA-C). For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, can delay the onset, reduce the severity, or eliminate the propensity for increased language deterioration, gait exacerbation, and/or fall associated with MSA-C, or delay or reverse its progression.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats gait exacerbations, increased fall liability and/or language deterioration associated with frontotemporal dementia with parkinsonism. For example, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof may delay the onset, reduce the severity or eliminate, or delay or reverse the progression of worsening gait, increased tendency to fall, and/or language deterioration associated with frontotemporal dementia with parkinsonism.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats increased fall propensity and/or worsening gait associated with corticobasal degeneration syndrome. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, can delay the onset, reduce the severity, or eliminate the increased propensity to fall and/or worsening gait associated with corticobasal degeneration syndrome, or delay or reverse its progression.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats gait disturbances associated with progressive supranuclear palsy. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay the onset, reduce the severity, or eliminate the progression of gait exacerbations associated with progressive supranuclear palsy.

In one embodiment, leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof treats the vibratory hallucinations, spatial orientation deterioration, visual deterioration, and/or increased postural sway associated with hypothalamic nystagmus. For example, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, may delay the onset, reduce the severity, or eliminate the progression of visual oscillations, spatial orientation deterioration, visual deterioration, and/or increased postural sway associated with cerebellar nystagmus.

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

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

Also disclosed is a kit for treating a neurodegenerative disease in a subject comprising a component for diagnosing or prognosing the disorder/condition, and leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof.

A component for diagnosing or prognosing a neurodegenerative disease may comprise a specific binding agent, probe, primer pair or primer combination, enzyme or antibody (including antibody fragment) capable of detecting or aiding in the detection of a neurodegenerative disease as defined herein. The kit may compriseIt is a fluorescent marker and is commercially available from Invitrogen and Lonza.And may be blue, bluish-white, yellow, green or red.

The kit further comprises leucine, acetyl-leucine or a pharmaceutically acceptable salt thereof as defined herein. The kit may further comprise a buffer or an aqueous solution. The kit may further comprise instructions for using leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof in the methods of the invention.

In yet another embodiment, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of providing neuroprotection in a subject in need thereof (e.g., a subject having, suspected of having, or at risk of having a neurodegenerative disease) is disclosed.

As used herein, "neuroprotection" and its synonyms refer to the prevention, slowing and/or reversal of the progression of neurodegeneration, including but not limited to, progressive loss of neuronal structure, progressive loss of neuronal function, and/or progressive neuronal death. Providing neuroprotection may result in delaying the onset of a neurodegenerative disease or one or more symptoms of a neurodegenerative disease that would otherwise be expected to manifest as typical disease progression, reducing the severity of a neurodegenerative disease, or reducing the severity of or eliminating one or more existing symptoms associated with a neurodegenerative disease, delaying the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease over time as compared to typical disease progression, and/or reversing the progression of one or more symptoms of a neurodegenerative disease or a neurodegenerative disease over time. The time to provide neuroprotection may be consistent with the duration of treatment described herein. Treatment may provide neuroprotection for a duration 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. Treatment may provide neuroprotection for a duration of about 3 months or more, about 4 months or more, about 5 months or more, or about 6 months or more. It may provide neuroprotection for a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment may provide neuroprotection during the life of the patient.

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

Also disclosed is a kit for providing neuroprotection in a subject in need thereof (e.g., a subject having, suspected of having, or at risk of having a neurodegenerative disease), the kit comprising a component for diagnosing or prognosing the disease/disorder, and leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof.

The disclosure also includes the use of leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof, as a neuroprotective agent in a subject in need thereof (e.g., a subject having, suspected of having, or at risk of having a neurodegenerative disease).

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