Combination of acetyl leucine and 4-aminopyridine or acetazolomide to treat ataxia

Abstract

The present description provides methods of treatment for ataxia in a subject in need of it to administer a combination of acetyl-leucine and 4-aminopyridine or a combination of acetyl-leucine and acetazolamide to the subject.

Description

Combination of acetyl leucine and 4-aminopyridine or acetazolomide to treat ataxia FIELD OF INVENTION

[0001] The present description provides a combination of acetyl-leucine and 4-aminopyridine or the combination of acetyl-leucine and acetazolamide to treat ataxia, for example, episodic ataxia, in a subject. BACKGROUND OF THE INVENTION

[0002] Ataxia can be hereditary or acquired. Hereditary ataxias, a group of genetic disorders characterized by slowly progressive incoordination of gait often associated with poor coordination of hands, speech, and eye movements and / or cerebellar atrophy, include autosomal dominant ataxias, e.g., spinocerebellar ataxias or episodic ataxias, and autosomal recessive ataxias, e.g., Niemann-Pick disease, gangliosidosis, or ataxia telangiectasia. Bird TD. Hereditary Ataxia Overview. 1998 Oct 28 (Updated 2019 Jul 25). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® (Internet). Seattle (WA): University of Washington, Seattle; 1993-2020. Acquired ataxias include sporadic ataxias or multiple system atrophies (MSA). Ashizawa and Xia, Continuum (Minneap Min) 22:1208-1226 (2016).

[0003] Episodic ataxias (EAs) are rare inherited neurological disorders characterized by recurrent episodes of cerebellar ataxia with postural and gait imbalance, limb ataxia, dysarthria, and nystagmus. EAs are often triggered by physical or emotional stress or alcohol and are accompanied by nausea and vomiting. Kipfer and Strupp, Movement Disorders Clinical Practice 1:285-290, doi:10.1002 / mdc3.12075 (2014); Jen and Wan, Handbook of Clinical Neurology 155:205-215, doi:10.1016 / b978-0-444-64189-2.00013-5 (2018).

[0004] There are eight known subtypes of AD. Among them, AD1 and AD2 are the most clinically relevant. AD2 typically begins in adolescence, but some cases with late onset have been reported. Imbrici et al., Neurology 65:944-946, do1:10.1212 / 01 .wnl.0000176069.64200.28 (2005). AD2 episodes generally last from minutes to hours and are accompanied by migraine-like headache in about 50% of patients. Jen et al., Neurology 62:17-22. do1:10.1212 / 01 .wnl.0000101675.61074.50 (2004). Patients with EA2 frequently develop slowly progressive interictal basal ataxia and various central oculomotor dysfunctions, for example mainly downward gaze nystagmus. Riant et al., Revue Neurologique 167:401-407, doi:10.1016 / j.neurol.2010.10.016 (2011).ASD2 is an inherited autosomal dominant channelopathy caused by mutations affecting the CACNA1A gene on chromosome 19p13, which encodes the alpha-1A subunit of the P / Q-type voltage-gated calcium channel (Cav2.1). Ophoff et al., Cell 87:543-552. doi:10.1016 / s00928674(00)81373-2 (1996). Therapeutic principles in patients with ASD include medical treatment and physical therapy, occupational therapy to preserve gait function, and speech therapy. Ilg et al., Cerebellum (London, England) 13:248-268, doi:10.1007 / s12311-013-0531-6 (2014); Gandini et al., J Neurol. 267:1211-1220, doi: 10.1007 / S00415-020-09717-3 (2020).

[0005] There is a need in the state of the art for novel medical therapies to treat ataxia in a QQhb ίη / 77Π7 / Ε / ΥΙΛΙ subject. BRIEF DESCRIPTION OF THE INVENTION

[0006] The applicant has unexpectedly discovered that acetyl-leucine can be combined with 4-aminopyridine (4-AP) or acetazolamide to treat ataxia in a subject in need of such treatment, including, but not limited to, episodic ataxia (EA). In some modalities, the subject has a cytosine and thymidine deletion at position 2070-2071 in exon 16 of the CACNA1A gene.

[0007] In one aspect, the present description provides acetyl-leucine combined with 4-AP for use in the treatment of ataxia in a subject.

[0008] In one aspect, the present description provides acetyl-leucine combined with acetazolamide for use in the treatment of ataxia in a subject.

[0009] In another respect, the present description provides a method of treating ataxia in a subject in need thereof, the method comprising administering a combination of a therapeutically effective amount of acetyl-leucine and a therapeutically effective amount of 4-AP to the subject.

[0010] In another respect, the present description provides a method of treating ataxia in a subject in need thereof, the method comprising administering the combination of a therapeutically effective amount of acetyl-leucine and a therapeutically effective amount of acetazolamide to the subject.

[0011] In another aspect, the present description provides the combination of acetyl-leucine and 4-AP for first-line therapy to treat ataxia.

[0012] In another aspect, the present description provides the combination of acetyl-leucine and acetazolamide for first-line therapy to treat ataxia.

[0013] In another aspect, the present description provides a kit comprising acetyl-leucine and 4-AP for treating ataxia in a subject.

[0014] In another aspect, the present description provides a kit comprising acetyl-leucine and acetazolamide for treating ataxia in a subject.

[0015] It should be understood that both the above summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE FIGURES

[0016] Figure 1 is a pedigree chart of a German family carrying a recently identified heterozygous autosomal dominant CACNA1A mutation (NM_001127221.1: (c2070_2071delinsGGAG, p.(Phe690Leufs*9))). This mutation was found in four family members across three generations, exhibiting a heterozygous phenotype. Legend: * = Index patient, square = male, circle = female, filled symbol = genetically affected subject, blank symbol = genetically unaffected subject. DETAILED DESCRIPTION OF THE INVENTION

[0017] In one modality, the present description provides acetyl-leucine combined with 4-AP or acetazolamide for use in the treatment of ataxia in a subject. This is referred to as Modality 1.

[0018] The present description provides Particular Modalities 2-23 as follows.

[0019] Modality 2. The combination for use in accordance with Modality 1, wherein acetyl-leucine and 4-AP QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ or acetazolamide are administered simultaneously.

[0020] Modality 3. The combination for use in accordance with Modality 2, wherein acetyl-leucine and 4-AP or acetazolamide are administered as a single pharmaceutical formulation.

[0021] Modality 4. The combination for use in accordance with Modality 2, wherein acetyl-leucine and 4-AP or acetazolamide are administered as two separate pharmaceutical formulations.

[0022] Modality 5. The combination for use according to Modality 1, wherein acetyl-leucine and 4-AP or acetazolamide are administered sequentially.

[0023] Modality 6. The combination for use in accordance with Modality 5, wherein acetyl-leucine is administered to the subject prior to 4-AP or acetazolamide.

[0024] Modality 7. The combination for use in accordance with Modality 5, wherein acetyl-leucine is administered to the subject after 4-AP or acetazolamide.

[0025] Modality 8. The combination for use in accordance with any of Modalities 5-7, wherein acetyl-leucine and 4-AP or acetazolamide are administered from approximately 1 minute to approximately 6 hours apart.

[0026] Modality 9. The combination for use according to Modality 8, wherein acetyl-leucine and 4-AP or acetazolamide are administered approximately 1 minute to 3 hours apart.

[0027] Modality 10. The combination for use according to Modality 9, wherein acetyl-leucine and 4-AP or acetazolamide are administered approximately 1 minute to 1 hour apart.

[0028] Modality 11. The combination for use in accordance with any of Modalities 1-10, wherein acetyl-leucine and 4-AP or acetazolamide are administered orally.

[0029] Modality 12. The combination for use in accordance with any of Modalities 1-11, wherein acetyl-leucine is administered once, twice, or three times per day.

[0030] Modality 13. The combination for use in accordance with any of Modalities 1-12, wherein 4-AP or acetazolamide is administered once, twice, or three times daily.

[0031] Modality 14. The combination for use in accordance with any of Modalities 1-13, wherein approximately 3 g to approximately 15 g of acetyl-leucine are administered per day.

[0032] Modality 15. The combination for use in accordance with any of Modalities 1-14, wherein approximately 10 mg to approximately 30 mg of 4-AP or approximately 500 mg to approximately 1000 mg of acetazolamide is administered daily.

[0033] Modality 16. The combination for use in accordance with any of Modalities 1-15, wherein acetyl-leucine and 4-AP or acetazolamide are administered as first-line therapy to treat ataxia.

[0034] Modality 17. The combination for use in accordance with any of Modalities 1-16, where the ataxia is EA.

[0035] Modality 18. The combination for use in accordance with Modality 17, where the EA is episodic ataxia type 2 (EA2).

[0036] Mode 19. The combination for the use of any of Modes 1-18, wherein the acetyl QQhb ίη / 77Π7 / Ε / ΥΙΛΙ leucine combines with 4-AP.

[0037] Modality 20. The combination for use of any of Modalities 1-18, wherein acetylleucine is combined with acetazolamide.

[0038] Modality 21. The combination for use in accordance with any of Modalities 1-20, wherein the acetyl-leucine is N-acetyl-DL-leucine.

[0039] Modality 22. The combination for the use of any of Modalities 1-20, wherein the acetyl-L-leucine is N-acetyl-L-leucine.

[0040] Modality 23. The combination for the use of any of Modalities 1-22, wherein the subject has a cytosine and thymidine deletion at position 2070-2071 in exon 16 of the CACNA1A gene.

[0041] In another modality, the present description provides a method of treating ataxia in a subject in need thereof, the method comprising administering to the subject a combination of a therapeutically effective amount of acetyl-leucine and (i) a therapeutically effective amount of 4-AP; or (ii) a therapeutically effective amount of acetazolamide. This is referred to as Modality I.

[0042] The present description provides particularly the Modalities ll-XXVI as follows.

[0043] Modality II. The method of Modality I, wherein acetyl-leucine and 4-AP or acetazolamide are administered simultaneously.

[0044] Modality III. The method of Modality II, wherein acetyl-leucine and 4-AP or acetazolamide are administered as a single pharmaceutical formulation.

[0045] Modality IV. The method of Modality II, wherein acetyl-leucine and 4-AP or acetazolamide are administered as two separate pharmaceutical formulations.

[0046] Modality V. The method of Modality I, wherein acetyl-leucine and 4-AP or acetazolamide are administered sequentially.

[0047] Modality VI. The Modality V method, wherein acetyl-leucine is administered prior to 4-AP or acetazolamide.

[0048] Modality Vil. The Modality V method, wherein acetyl-leucine is administered after 4-AP or acetazolamide.

[0049] Modality VIII. The method of any of Modalities V-VII, wherein acetyl-leucine and 4-AP or acetazolamide are administered from approximately 1 minute to approximately 6 hours apart.

[0050] Modality IX. The method of Modality VIII, wherein acetyl-leucine and 4-AP or acetazolamide are administered approximately 1 minute to 3 hours apart.

[0051] Modality X. The method of Modality IX, wherein acetyl-leucine and 4-AP or acetazolamide are administered approximately 1 minute to 1 hour apart.

[0052] Modality XI. The method of any of the Modalities IX, wherein acetyl-leucine and 4-AP or acetazolamide are administered orally.

[0053] Modality XII. The method of any of Modalities I-XI, wherein acetyl-leucine is administered once, twice, or three times per day. QQhb ίη / 77Π7 / E / YΙΛΙ

[0054] Modality XIII. The method of any of Modalities I-XII, wherein 4-AP or acetazolamide is administered once, twice, or three times per day.

[0055] Modality XIV. The method of any of Modalities l-XIII, where approximately 3 g to approximately 15 g of acetyl-leucine are administered per day.

[0056] Modality XV. The method of any of Modalities I-XIV, wherein approximately 10 mg to approximately 30 mg of 4-AP or approximately 500 mg to approximately 1000 mg of acetazolamide is administered per day.

[0057] Modality XVI. The method of any of Modalities I-XV, wherein acetyl-leucine and 4-AP or acetazolamide are administered as first-line therapy to treat ataxia.

[0058] Modality XVII. The method of any of the Modalities l-XVI, where the ataxia is EA.

[0059] Modality XVIII. The method of any of the Modalities l-XVIl, where EA is episodic ataxia type 2 (EA2).

[0060] Modality XIX. The method of any of Modalities I-XVII, wherein a therapeutically effective amount of acetyl-leucine is administered with a therapeutically effective amount of 4-AP.

[0061] Modality XX. The method of any of Modalities l-XIX, wherein a therapeutically effective amount of acetyl-leucine is administered with a therapeutically effective amount of acetazolamide.

[0062] Modality XXI. The method of any of the Modalities l-XX, where acetyl-leucine is N-acetyl-DLleucine.

[0063] Modality XXII. The method of any of the Modalities l-XX, where acetyl-leucine is N-acetyl-leucine.

[0064] Modality XXIII. The method of any of Modalities I-XXII, wherein the subject has a deletion of cytosine and thymidine at position 2070-2071 in exon 16 of the CACNA1A gene.

[0065] Modality XXIV. A kit comprising acetyl-leucine and 4-AP or acetazolamide for treating ataxia in a subject.

[0066] Modality XXV. The Modality XXIV kit which also includes instructions for administering acetyl-leucine and 4-AP or acetazolamide to the subject.

[0067] Modality XXVI. The modality XXIV or XXV team, where the ataxia is episodic ataxia type 2. Definitions

[0068] As used herein, the singular forms “a”, “an” and “the” include reference to the plural.

[0069] As used herein, the terms “approximately” and “around” shall be understood to encompass generally ± 20% of the specified quantity, frequency, or value. Numerical quantities provided herein are approximate unless otherwise stated, meaning that the term “around” or “approximately” may be inferred where not expressly stated.

[0070] The terms “administer,” “administration,” or “administering” as used herein refer to (1) providing, giving, dosing, and / or prescribing by any health care professional or their authorized agent or under their direction, the combination of acetyl-leucine and 4-AP or acetazolamide and (2) placing in, taking, or consuming by the subject or QQhb ίΠ / ZZΖηZ / E / YΙΛΙ person by herself by herself, acetyl-leucine and 4-AP or acetazolamide. Any reference to acetyl-leucine, 4-AP or acetazolamide includes the pharmaceutically acceptable salts thereof, even if not expressly stated.

[0071] A “pharmaceutically acceptable salt” as referred to herein, is any salt preparation that is appropriate for use in a pharmaceutical application.Pharmaceutically acceptable salts include, but are not limited to, amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidine-T-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane and the like; alkali metal salts such as lithium, potassium, sodium and the like; ferrous alkali 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; mineral acids such as hydrochlorides, sulfates and the like; and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and the like.

[0072] Acetylleucine and 4-AP or acetazolamide may be formulated and administered to a subject in accordance with known teachings in the prior art. For example, acetylleucine and 4-AP or acetazolamide may be formulated as separate pharmaceutical compositions. The pharmaceutical compositions may comprise the active agent, i.e., acetylleucine or 4-AP or acetazolamide, and one or more pharmaceutically acceptable carriers. Acetylleucine and 4-AP or acetazolamide may also be formulated as a single pharmaceutical composition comprising both active agents and one or more pharmaceutically acceptable carriers.

[0073] Pharmaceutical compositions comprising acetyl-leucine and 4-AP or acetazolamide, whether separate or combined in a single composition, may take any of a number of different forms depending on the form in which they are to be used. Thus, for example, the pharmaceutical compositions may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension, or any other suitable form that may be administered to a subject in need of treatment.

[0074] A “pharmaceutically acceptable carrier,” as referred to herein, is any known compound or combination of known compounds, e.g., excipients, carriers, etc., that are known to those skilled in the art to be useful in the formulation of pharmaceutical compositions. It is appreciated that the carrier of the pharmaceutical composition should be one that is tolerated by the subject to whom it will be provided.

[0075] In one embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable carrier may include, but is 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, coatings, or tablet disintegrants. The carrier may also be an encapsulating material. In powders, the carrier QQhb ίη / ZZΖΠZ / E / YΙΛΙ may be a finely divided solid mixed with the finely divided active agents according to the invention. In tablets, the active agent may be mixed with a carrier having the necessary compressibility properties in suitable proportions and compacted into the desired shape and size. The powders and tablets may, for example, contain up to 99% of the active agents. 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 embodiment, the pharmaceutically acceptable carrier may be a gel, and the composition may be in the form of a cream or similar.

[0076] The carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like.

[0077] 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 and / or 4-AP or acetazolamide may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils and fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmoregulators.Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives such as those mentioned above, e.g., cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis 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 in the form of sterile liquids for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or another pharmaceutically acceptable propellant.

[0078] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, may be used, for example, for intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and subcutaneous injection. The active agent may be prepared as a sterile solid composition that can be dissolved or suspended at the time of administration using sterile water, saline solution, or another appropriate sterile injectable medium.

[0079] The compositions may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monooleate, polysorbate 80 (esters of sorbitol oleate and its anhydrides copolymerized with ethylene oxide), and the like. The compositions may also be administered orally in either liquid or solid form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, or powders, and liquid forms such as solutions, syrups, elixirs, and suspensions. Forms suitable for parenteral administration include sterile solutions, QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ emulsions and suspensions.

[0080] In one embodiment, the pharmaceutical composition of acetyl-leucine, 4-AP, and acetazolamide is an oral dosage form, such as a tablet. In tablets, the active agent may be mixed with a vehicle, such as a pharmaceutically acceptable carrier, having the necessary compressibility properties in suitable proportions and compacted into the desired shape and size. The tablets may contain up to 99% by weight of the active agents.

[0081] Pharmaceutical compositions in solid oral dosage form, such as tablets, may be prepared by any method known in the pharmaceutical arts. Pharmaceutical compositions are usually prepared by mixing the active agent with conventional, pharmaceutically acceptable carriers.

[0082] A tablet comprising acetyl-leucine may be formulated as known in the prior art. Tanganil®, for example, includes wheat starch, pregelatinized corn starch, calcium carbonate, and magnesium stearate as excipients. The same or similar excipients may be used, for example, with the present description.

[0083] The composition of each 700 mg Tanganil® tablet is as follows: 500 mg of acetyl-DL-leucine, 88 mg of wheat starch, 88 mg of pregelatinized maize starch, 13 mg of calcium carbonate, and 11 mg of magnesium stearate. The same tablets may be used, for example, in the methods described herein.

[0084] As discussed above, acetyl-leucine and 4-AP or acetazolamide can be formulated or administered as a pharmaceutical composition in any number of different forms. For example, acetyl-leucine can be formulated as a pharmaceutical composition to facilitate its release across the blood-brain barrier. As a further example, acetyl-leucine can be formulated as a pharmaceutical composition bypassing the blood-brain barrier.

[0085] In one embodiment, the pharmaceutical composition, for example, comprising acetyl-L-leucine or a salt thereof, is formulated for nanodelivery, for example, colloidal drug-carrying systems. Suitable examples include, but are not limited to, liposomes, nanoparticles (for example, polymeric, lipid, and inorganic nanoparticles), nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots. See, for example, Patel et al., “Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain,” CNS Drugs 31:109-133 (2017); Kabanov et al., “New Technologies for Drug Delivery across the Blood-Brain Barrier,” Curr Pharm Des., 10(12):1355-1363 (2004); Cheng et al., “Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro BloodBrain Barrier Model and in Alzheimer's Disease Tg2576 Mice,” The AAPS Journal, vol. 15, no. 2, pp. 324-336 (2013); Láhde et al.“Production of L-Leucine Nanoparticles under Various Conditions Using an Aerosol Flow Reactor Method,” Journal of Nanomaterials, vol. 2008, article ID 680897 (2008).

[0086] In one embodiment, the pharmaceutical composition, for example, comprising N-acetyl-L-leucine or a salt thereof, is formulated for direct delivery to the central nervous system (CNS), for example, by injection or infusion. Formulations for and methods of direct delivery to the CNS are known in the prior art. See, for example, U.S. Patent No. 9,283,181. Examples of such administration include, but are not limited to, intranasal, intraventricular, intrathecal, intracranial, and delivery via a nasal mucosal graft. In one embodiment, the pharmaceutical composition is administered by intracerebroventricular infusion. QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ

[0087] In one embodiment, the pharmaceutical composition is formulated for (and administered by) intranasal delivery. See, for example, Hanson et al., Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease, BMC Neurosci. 9(Suppl 3):S5 (2008). In one embodiment, the pharmaceutical composition is formulated for (and administered by) delivery through a nasal mucosal graft. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intracerebroventricular injection or infusion. In another embodiment, the pharmaceutical composition is formulated for (and administered by) intracisternal intrathecal injection or infusion. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal lumbar injection or infusion.

[0088] Various techniques may be used, including, without limitation, injection through an orifice or cystic or lumbar puncture or similar, as known in the prior art. Various delivery devices may be used, either internal (e.g., implanted) or external, as known in the prior art, such as pumps, catheters, reservoirs, etc. In one modality, the administration interval is once every two weeks.

[0089] The term “ataxia” refers to impaired coordination of voluntary muscle movement in an individual. Ataxias can be hereditary or acquired. Hereditary ataxias, a group of genetic disorders characterized by slowly progressive incoordination of gait, are often associated with poor coordination of hand movements, speech, and eye movements and / or cerebellar atrophy. They include autosomal dominant ataxias, such as spinocerebellar or episodic ataxias, and autosomal recessive ataxias, such as Niemann-Pick disease, gangliosidosis, or ataxia telangiectasia. Bird TD. Hereditary Ataxia Overview. 1998 Oct 28 (Updated July 25, 2019). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® (Internet). Seattle (WA): University of Washington, Seattle; 1993-2020; Beaudin etal., 4:3 https: / / doi.Org / 10.1186 / s40673-017-0061y (2017).Acquired ataxias include sporadic ataxias or multiple system atrophies (MSA). Ashizawa and Xia, Continuum (Minneap Min) 22:1208-1226 (2016). In one modality, the ataxia is episodic ataxia, e.g., episodic ataxia type 1 to 7. In another modality, the episodic ataxia is episodic ataxia type 1 or type 2. In another modality, the episodic ataxia is episodic ataxia type 2. In yet another modality, the subject has a mutation in the CACNA1A gene, which mutation may include, but is not limited to, one or more of those described in Sintas et al., Sel Rep 7:2514 doi: 10.1038 / s41598-017-02554-x (2017). In another modality, the subject has a deletion of cytosine and thymidine at position 2070-2071 in exon 16 of the CACNA1A gene. Kim et al., J Clin Neurol 2:268-271 (2006); Denier et al., Neurology;52:1816-1821 (1999).

[0090] The term “episodic ataxia” or “EA” refers to a condition characterized by episodes of ataxia and incoordination lasting from minutes to hours. Eight subtypes of episodic ataxia have been defined according to clinical or genetic characteristics. Episodic ataxia type 2 (EA2) is the most common subtype. Episodes of EA2 are characterized by recurrent ataxia, slurred speech lasting several hours, and interictal nystagmus. Onset is typically early in life, but much later onset has also been reported. Vertigo and fluctuating general weakness are common. Other symptoms include, but are not limited to, dysarthria, diplopia, tonic upward gaze, headache, seizures, dystonia, and / or cognitive impairment. Choi and Choi, J Mov Disord 9:129-135, DOI: https: / / do¡.org / 10.14802 / jmd .16028 (2016). QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ

[0091] The term “acetyl-leucine” refers collectively to N-acetyl-DL-leucine (ADLL) or a pharmaceutically acceptable salt thereof; N-acetyl-D-leucine (ADL) or a pharmaceutically acceptable salt thereof; and N-acetyl-L-leucine (ALL) or a pharmaceutically acceptable salt thereof. The term acetyl-leucine includes isotopically labeled analogues of N-acetyl-DL-leucine, N-acetyl-D-leucine, and N-acetyl-L-leucine, wherein one or more atoms are replaced by an atom having a different atomic mass or mass number. Isotopes that may be incorporated include isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, and 17O. In one embodiment, an isotopically labeled analogue of acetyl-leucine is provided, wherein substantially all atoms at a position within acetyl-leucine are replaced by an atom having a different atomic mass or mass number.In another embodiment, an isotopically labeled analogue of acetyl-leucine is provided, in which a portion of the atoms at a position within the acetyl-leucine are replaced; for example, the acetyl-leucine is enriched at one or more positions with an atom having a different atomic mass or mass number. The isotopically labeled acetyl-leucine can be prepared by methods known in the prior art.

[0092] In one form, N-acetyl-DL-leucine, N-acetyl-D-leucine or N-acetyl-L-leucine is not isotopically labeled.

[0093] In one embodiment, the isotopically labeled analogue is a deuterated analogue of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine, wherein one or more hydrogen atoms are replaced with deuterium. In one embodiment, one hydrogen atom of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine is replaced with deuterium. In another embodiment, two hydrogen atoms of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine are replaced with deuterium. In another embodiment, three hydrogen atoms of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine are replaced with deuterium. In one embodiment, four hydrogen atoms of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine are replaced with deuterium. In another embodiment, five hydrogen atoms of N-acetyl-DL-leucine, N-acetyl-D-leucine, or N-acetyl-L-leucine are replaced with deuterium.In another form, six hydrogen atoms of N-acetyl-DL-leucine, N-acetyl-D-leucine or N-acetyl-L-leucine are replaced with deuterium.

[0094] In one embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-DL-leucine or a deuterated analogue thereof. In another embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-D-leucine or a deuterated analogue thereof. In another embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-L-leucine or a deuterated analogue thereof.

[0095] In another embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-DL-leucine. In another embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-D-leucine. In another embodiment, the acetyl-leucine used in the methods described herein is N-acetyl-L-leucine.

[0096] The terms “4-aminopyridine”, “4-AP”, or “4AP” refer to the drug also known as fampridine, dalfampridine, or Ampyra®. The chemical structure of 4-AP is: QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ

[0097] The term “acetazolamide” refers to the drug known as Diamox. The chemical structure of acetazolamide is: QQhb ίη / ΖΖΠΖ / Ε / ΥΙΛΙ

[0098] “Administered in combination” and similar phrases means that two agents, for example, acetyl-DL-leucine, acetyl-D-leucine, or acetyl-L-leucine; and (i) 4-AP; or (ii) acetazolamide are administered concurrently to the subject being treated. In one modality, acetyl-DL-leucine, acetyl-D-leucine, or acetyl-L-leucine and 4-AP or acetyl-DL-leucine, acetyl-D-leucine, or acetyl-L-leucine and acetazolamide are administered in combination with a first-line therapy for treating AS, for example, AS2. In some modalities, the subject does not respond to treatment with 4-AP as a single agent and / or experiences undesirable side effects. In some modalities, the subject does not respond to treatment with acetazolamide as a single agent and / or experiences undesirable side effects.

[0099] “First-line therapy” means a treatment regimen generally accepted or recommended by medical establishments or a regulatory authority, e.g., the U.S. Food and Drug Administration or the European Medicines Agency, for the initial treatment of a condition, disease, or disorder.

[0100] “Concurrently” means that each active agent is administered either (i) simultaneously; or (ii) sequentially in any order at different points in time. A combination of two agents is considered to be administered simultaneously if each agent is administered to the subject less than 1 minute apart. If not administered simultaneously, it means that both agents are administered to a subject in a sequence and close enough in time to provide the desired therapeutic effect and can act in concert to treat the AD.

[0101] In one embodiment, acetyl-leucine and 4-AP or acetazolamide are administered separately, in any appropriate form and by any suitable route. In one embodiment, both acetyl-leucine and 4-AP or acetazolamide are administered orally to the subject as tablets or capsules.

[0102] In one modality, acetyl-leucine is administered to the subject from 1 minute to 24 hours before the administration of 4-AP or acetazolamide to the subject. For example, acetyl-leucine is administered 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours before the administration of 4-AP or acetazolamide to a subject.

[0103] In another modality, acetyl-leucine is administered simultaneously with 4-AP or acetazolamide to the subject.

[0104] In another embodiment, acetyl-leucine is administered to the subject from 1 minute to 24 hours after the administration of 4-AP or acetazolamide to the subject. For example, acetyl-leucine is administered 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours after the administration of 4-AP or acetazolamide to a subject.

[0105] In another modality, acetyl-leucine and 4-AP or acetazolamide are administered to the subject approximately 1 minute to approximately 24 hours apart. For example, acetyl-leucine and 4-AP or acetazolamide are administered approximately 1 minute apart, 5 minutes apart, 10 minutes apart, 30 minutes apart, 45 minutes apart, 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, or 11 to 12 hours apart.

[0106] “Subject” means a human.

[0107] “Subject in need of the same” means a human who has ataxia and needs the treatment.

[0108] A “therapeutically effective amount” of acetyl-leucine or 4-AP or acetazolamide means any amount of each active agent that, when administered to a subject, is the amount necessary to produce the desired effect, which, for the purposes of this description, may be therapeutic and / or prophylactic. The dose may be administered according to various parameters, such as the specific active agent used; the age, weight, and condition of the patient to be treated; the route of administration; and the required regimen. A physician will be able to determine the route of administration and required dose for any particular patient. For example, a daily dose of each active agent may be from approximately 0.1 to approximately 225 mg per kg, from approximately 1 to approximately 150 mg per kg, or from approximately 10 to approximately 100 mg per kg of body weight.

[0109] As used herein, “treat” or “treatment” means any indication of success in preventing, stopping, or improving a disease, disorder, condition, or syndrome, e.g., ataxia, in a subject and / or preventing, stopping, or improving any one or more symptoms of a disease, disorder, condition, or syndrome in a subject, including any objective or subjective parameter such as the abatement; remission; prevention, decrease, inhibition, or elimination of one or more symptoms, e.g., migraine; making the disease, disorder, condition, or syndrome more tolerable to the subject; slowing the worsening of the disease, disorder, condition, or syndrome; or improving the physical or mental well-being of the subject in need thereof.

[0110] The terms “treat” or “treatment” also encompass the induction of inhibition, regression, or stasis of the disease, disorder, condition, or syndrome. For example, the treatment of a subject in need of treatment for ataxia includes reducing the episodes of ataxia in the subject, inducing a clinical response, inhibiting or reducing the progression of episodic ataxia, or inhibiting or reducing one or more complications of ataxia.

[0111] The prevention, arrest, or improvement of an injury or pathology of a disease, disorder, condition, or syndrome, such as the prevention, reduction, inhibition, or elimination of one or more symptoms of a disease, disorder, condition, or syndrome, may be based on objective and / or subjective parameters, including, for example, the results of physical examinations, neurological examinations, and / or psychiatric evaluations. The success of treatment for certain diseases, for example, ataxia, for example, Alzheimer's disease, may be measured or evaluated, for example, by comparing the severity of the disease, for example, the objective and / or subjective parameters of ataxia, before initiating treatment with acetyl-leucine and 4-AP or acetazolamide, with the severity of the disease after the initiation of treatment. QQhb iP / ZZΖ / E / YILI treatment with acetyl-leucine and 4-AP or acetazolamide. For example, the severity of ataxia can be assessed using a scale, index, classification, or score. In one modality, the treatment described herein improves that assessment from a value or grade characteristic of a symptomatic subject to a value or grade characteristic of a non-symptomatic subject. In another modality, the treatment described herein improves that assessment compared to a baseline value. The baseline value may be, for example, the subject's condition before initiating any treatment for the disease or before initiating treatment for the disease with acetyl-leucine and 4-AP or acetazolamide. Alternatively, the baseline value may be, for example, the subject's condition after a certain period of time on treatment for the disease.In one modality, treatment with acetyl-leucine and 4-AP or acetazolamide as described herein improves the subject's assessment (e.g., scale, index, classification, or score of objective and / or subjective parameters, e.g., SARA) compared to a baseline value by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In another modality, the assessment improves by at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0112] In one formulation, acetyl-leucine is administered at a dose ranging from approximately 500 mg to approximately 30 g per day. For example, acetyl-leucine is administered at a dose ranging from approximately 500 mg to approximately 15 g per day, or at a dose ranging from approximately 1.5 g to approximately 10 g per day, optionally by solid or liquid oral route. N-Acetyl-DL-leucine may be administered, for example, at a dose similar to that of Tanganil®, which is prescribed to adults at a dose of 1.5 g to 2 g per day, 3-4 tablets in two doses, in the morning and at night.

[0113] If only one enantiomer of acetyl-leucine is administered, that is, N-acetyl-D-leucine or N-acetyl-L-leucine, the doses may be reduced accordingly. For example, if only N-acetyl-L-leucine or only N-acetyl-D-leucine is administered, the dose may range from approximately 250 mg to approximately 15 g per day, from approximately 250 mg to approximately 10 g per day, or from approximately 250 mg to approximately 5 g per day, or from approximately 0.75 g to approximately 5 g per day.

[0114] In one modality, the administered dose ranges of acetyl-leucine are approximately 1 g to approximately 30 g per day. For example, the administered dose ranges of acetyl-leucine are approximately 1 g to approximately 15 g per day, approximately 1 g to approximately 10 g per day, or approximately 1.5 g to approximately 7 g per day, 15.1 g to approximately 30 g per day, 16 g to approximately 30 g per day, 17 g to approximately 30 g per day, 18 g to approximately 30 g per day, 19 g to approximately 30 g per day, or 20 g to approximately 30 g per day. They may be approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 g to approximately 15 g per day. They can be approximately 2, 3, 4, 5, 6, 7, 8, or 9 g up to approximately 10 g per day. They can be 15.1, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, or 29 g up to approximately 30 g per day.They can be more 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 modality, the dose ranges from approximately 4 g to approximately 6 g per day. In one modality, the dose ranges from approximately 4 g to approximately 5 g per day. In one modality, the dose is approximately 4.5 g per day. In one modality, the dose is approximately 5 g per day. In one modality, the. The dosage of QQhb ίη / ZZΖΠZ / E / YΙΛΙ is approximately 1 g per day, approximately 2 g per day, approximately 3 g per day, approximately 4 g per day, approximately 5 g per day, approximately 6 g per day, approximately 7 g per day, approximately 8 g per day, approximately 9 g per day, approximately 10 g per day, approximately 11 g per day, approximately 12 g per day, approximately 13 g per day, approximately 14 g per day, or approximately 15 g per day. In another form, the dosage is approximately 16 g per day, approximately 17 g per day, approximately 18 g per day, approximately 19 g per day, or approximately 20 g per day. In another form, the dose is approximately 21 g per day, approximately 22 g per day, approximately 23 g per day, approximately 24 g per day, approximately 25 g per day, approximately 26 g per day, approximately 27 g per day, approximately 28 g per day, approximately 29 g per day, or approximately 30 g per day.In one formulation, these doses are administered in a solid oral dosage form, especially tablets. In another formulation, these doses are for acetylleucine in its racemic form. Doses for acetylleucine when an enantiomeric excess is present may be lower, for example, about 50% lower. Dosage ranges described above that are halved are also explicitly covered by this description.

[0115] In one modality, 4-AP is administered at a dose ranging from approximately 0.01 mg to approximately 1 g per day, for example, from approximately 5 mg to approximately 100 mg per day, or from approximately 15 mg to approximately 30 mg per day. In another modality, 4-AP is administered at a dose of approximately 5 mg per day. In another modality, 4-AP is administered at a dose of approximately 10 mg per day. In another modality, 4-AP is administered at a dose of approximately 15 mg per day. In another modality, 4-AP is administered at a dose of approximately 20 mg per day. In another modality, 4-AP is administered at a dose of approximately 25 mg per day. In another modality, 4-AP is administered at a dose of approximately 30 mg per day. In another modality, 4-AP is administered in two divided doses.

[0116] In one formulation, acetazolamide is administered at a dose ranging from approximately 100 mg to approximately 2000 mg per day. In another formulation, acetazolamide is administered at a dose of approximately 250 mg per day. In another formulation, acetazolamide is administered at a dose of approximately 500 mg per day. In another formulation, acetazolamide is administered at a dose of approximately 750 mg per day. In another formulation, acetazolamide is administered at a dose of approximately 1000 mg per day.

[0117] In one modality, the total daily dose of acetyl-leucine or 4-AP or acetazolamide can be distributed over multiple administrations, meaning that administration can occur two or more times a day to achieve the total daily dose. As an example, the required number of tablets to provide the total daily dose of acetyl-leucine can be divided over two administrations (e.g., morning and evening) or three administrations (e.g., morning, afternoon, and evening). Each dose can be administered with or without food.For example, N-acetyl-L-leucine or N-acetyl-DL-leucine can be dosed approximately 1 or approximately 2 hours before food, such as at least approximately 20 minutes, at least approximately 30 minutes, at least approximately 40 minutes or at least approximately 1 hour before food, or it can be dosed approximately 1, approximately 2 or approximately 3 hours after food. QQhb ίη / ZZΖΠZ / E / YΙΛΙ food, such as waiting for example at least approximately 20 minutes, at least approximately 30 minutes, at least approximately 1 hour, at least approximately 1.5 hours, at least approximately 2 hours, or at least approximately 2.5 hours after food. For example, a total daily dose of 4.5 g of acetyl-DL-leucine can be administered as three Tanganil® tablets (or equivalent) before, with, or after breakfast, three additional tablets before, with, or after lunch, and three additional tablets before, with, or after dinner.

[0118] The duration of treatment for the combination of acetyl-leucine and 4-AP or acetazolamide can be approximately seven days or more. For example, the duration of treatment can be approximately two weeks or more, approximately three weeks or more, approximately one month or more, approximately six weeks or more, approximately seven weeks or more, or approximately two months or more. In one modality, the duration of treatment is approximately three months or more, for example, approximately four months or more, approximately five months or more, or approximately six months or more. The duration of treatment can also be approximately one year or more, approximately two years or more, approximately four years or more, approximately five years or more, or approximately ten years or more. The duration of treatment can also be for the lifetime of the subject.

[0119] Any and all combinations of dosage form, dose amount, dosage schedule, and duration of treatment for the combination of acetyl-leucine and 4-AP or acetazolamide are contemplated and covered by the description. In one form, the dose of acetyl-leucine is approximately 4 g to approximately 10 g per day, taken in one, two, or three divided doses per day, for a duration of treatment of approximately two months or more. In another form, the dose of acetyl-leucine is greater than 4 g but not greater than 5 g per day, taken in one, two, or three divided doses per day, for a duration of treatment of approximately six months or more. The dosage form may be an oral dosage form, especially tablets.

[0120] In one modality, the combination of acetyl-leucine and 4-AP or acetazolamide is used to treat ataxia or one or more symptoms of ataxia. In another modality, ataxia is EA. In yet another modality, EA is EA2. As used herein, “treating ataxia or one or more symptoms of ataxia” and the like refers to delaying the onset of ataxia or one or more symptoms of ataxia that would otherwise be expected to occur in accordance with the typical progression of the disease, reducing the severity of ataxia, or reducing the severity of or eliminating one or more of the existing symptoms associated with ataxia, delaying the progression of ataxia or one or more symptoms of ataxia over time compared to the typical progression of the disease, and / or reversing the progression of ataxia or one or more symptoms of ataxia over time.

[0121] A “symptom” of ataxia includes any clinical or laboratory manifestation associated with ataxia, such as poorly coordinated gait and finger / hand movements, dysarthria, nystagmus, etc., and is not limited to what the individual can feel or observe. For example, symptoms of Alzheimer's disease include, but are not limited to, vertigo, dysarthria, diplopia, weakness, tonic upward gaze, headache, seizures, dystonia, and / or cognitive impairment. The onset of symptoms can range from birth to adulthood.

[0122] the progression of ataxia or one or more of the symptoms of ataxia over time or through treatment The progression and / or severity of the disease can be monitored, for example, by using one or more known tests at two or more points in time and comparing the results. The progression and / or severity of the disease can be assessed, for example, using the Scale for the Evaluation of Ataxia Classification (SARA), Spinocerebellar Ataxia Functional Index (SCAFI), International Cooperative Ataxia Classification Scale (ICARS), Brief Ataxia Classification Scale (BARS), Modified Disability Classification Scale (mDRS), EuroQol 5Q-5D-5L (EQ-5D-5L), Visual Analogue Scale (VAS), Wechsler Adult Intelligence Scale-Revised (WAIS-R), Wechsler Intelligence Scale for Children-IV (WISC-IV), Montreal Cognitive Assessment (MoCA), or other appropriate tests. EXAMPLES EXAMPLE 1

[0123] A 47-year-old German woman presented with recurrent episodic attacks of postural imbalance (without vertigo sensu stricto, nausea, or vomiting) with a sensation of falling forward and associated holocephalic headache, which began around the age of 15. The attacks occurred daily, very often in stressful situations, and usually lasted for several hours. No other triggering factors were apparent. At the time of presentation, the patient experienced persistent dizziness and postural insecurity between attacks, making her dependent on regular assistance in her daily routine. There was no evidence of seizures or syncope in the patient. The diagnosis had remained unknown, and no specific treatment had been previously attempted.

[0124] The patient's clinical and neuro-ophthalmologic examination revealed cerebellar oculomotor dysfunction with bilateral horizontal evoked gaze and episodes of nystagmus, saccadic tracking in all directions, hypermetric horizontal saccadic movements, reduced optokinetic nystagmus in all directions, and bilateral horizontally reduced VOR. Finger-to-finger tracking showed slightly hypermetric movements. The Romberg test revealed an imbalance in tandem posture. Quantitative gait analysis with the GAITRite system showed a slightly reduced step speed and length, but no more aberrations than in his age cohort. His cranial MRI showed several small lesions in the suprasensory white matter, but no distinct vermian atrophy, as sometimes reported in AD2.

[0125] Genetic testing using next-generation sequencing and Sanger sequencing methods revealed a novel, heterozygous, pathogenic variant in exon 16 of the CACNA1A gene NM_001127221.1: (c2070_2071 delinsGGAG, p.(Phe690Leufs*9)). Cytosine and thymidine deletions were identified at position 2070-2071, along with a four-nucleotide insertion at this position in exon 16 of the CACNA1A gene. This leads to a frameshift during translation and early interruption of protein synthesis at codon 698 after the incorporation of eight altered amino acids.

[0126] The same heterozygous CACNA1A mutation was found in three other family members (Figure 1) of the patient. The clinical phenotypes varied considerably: The patient's 68-year-old mother suffered from a slowly progressive gait imbalance, first recognized at age 40, but without atoxic episodes and still lived independently. Our patient's 45-year-old brother reported no worsening of symptoms or episodes of ataxia, vertigo, or imbalance. He only reported having suffered QQhb ίη / ZZΖΠZ / E / YΙΛΙ of intermittent headache since early childhood, which had responded partially to ibuprofen. Our patient's 15-year-old nephew (her brother's son) had suffered from episodic attacks with gait imbalance, vertigo, and headache, typically lasting for several hours and triggered by tension since the age of 14.

[0127] One reason for this heterogeneous phenotype could be incomplete penetrance. Evidence of incomplete intrafamilial penetrance due to a pathogenic CACNA1A variant in exon 6 exists in the literature. Angelini et al., European Journal of Medical Genetics 62:103530. doi:10.1016 / j.ejmg.2018.08.011 (2019). However, the involvement of other genes cannot be ruled out. One of the main methodological limitations is the lack of general certainty regarding the coverage of a genetic mosaic.

[0128] The patient did not respond to treatment with 4-aminopyridine (20 mg / day) or acetazolamide (250 mg–500 mg / day). Griggs et al., Neurology 28:1259–1264. doi:10.1212 / wnl.28.12.1259 (1978). Acetazolamide also caused paresthesia and renal dysfunction as side effects that the patient did not tolerate, and therefore the dose was not increased further.

[0129] The patient was then treated with the combination of 4-aminopyridine (Fampyra™ (15 mg / day)) and acetyl-DL-leucine (5 g / day). During the subsequent 12-month observation period, a remarkable stabilization of objective clinical and functional measurements (such as videooculography, gait analysis, and ataxia scores (SARA scores of 4)) was observed, as well as a subjectively relevant improvement in the patient's daily routine between ictal intervals. No further disease progression has been observed. EXAMPLE 2

[0130] The patient is a 26-year-old man from Slovakia. Physical exercise and stress triggered vertigo and vomiting starting at age 8. By age 17, the patient was experiencing frequent vomiting, vertigo, ataxia, and slurred speech. The patient was diagnosed with episodic ataxia type 2. Without medication, the patient experienced one or two episodes of ataxia per day.

[0131] At the age of 18, the patient was treated with acetazolamide. The frequency of episodes decreased from two or three times per week for a period of time and then returned to a frequency of one ataxia episode per day.

[0132] The patient was treated with a combination of acetazolamide and 5 g per day of tanganil (acetyl-DL-leucine), and his condition stabilized. After 3 months of treatment, the patient experienced one episode of ataxia and two attacks of vertigo. The patient is also taking sertraline. Genetic testing showed that the patient had the CACNA1A p.Gly297Arg (c.889G>A) variant. REFERENCES

[0133] 1. KipferS, Strupp M (2014) The Clinical Spectrum of Autosomal-Dominant Episodic Ataxias. Movement disorders clinical practice 1 (4):285-290. doi:10.1002 / mdc3.12075

[0134] 2. Jen JC, Wan J (2018) Episodic ataxias. Handbook of clinical neurology 155:205-215. doi:10.1016 / b978-0-444-64189-2.00013-5

[0135] 3. Imbrici P, Eunson LH, Graves TD, Bhatia KP, Wadia NH, Kullmann DM, Hanna MG (2005) Late-onset QQhb ίη / 77Π7 / Ε / ΥΙΛΙ episodio ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology 65 (6):944-946. doi: 10.1212 / 01.wnl.0000176069.64200.28

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[0138] 6. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Franz Family Family (1996) migraine and episodio ataxia type-2 are caused by mutations in the Ca2+channel gene CACNL1A4. Cell 87 (3):543-552. do¡:10.1016 / s0092-8674(00)81373-2

[0139] 7. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW (2007) Primary episodio ataxias: diagnosis, pathogenesis and treatment. Brain 130 (Pt 10):2484-2493. do¡:10.1093 / brain / awm126

[0140] 8. Isaacs DA, Bradshaw MJ, Brown K, Hederá P (2017) Case report of novel CACNA1A gene mutatlon causing episodio ataxia type 2. SAGE open medical case reports 5:2050313x17706044. doi: 10.1177 / 2050313x17706044

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[0142] 10. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 17 (5):405-424. doi:10.1038 / gim.2015.30

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[0144] 12. Maksemous N, Roy B, Smith RA, Griffiths LR (2016) Next-generation sequencing identifies novel CACNA1A gene mutations in episode ataxia type 2. Molecular genetics & genomic medicine 4 (2):211–222. doi:10.1002 / mgg3.196

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[0151] 19. Kalla R, Strupp M (2019) Aminopyridines and Acetyl-DL-leucine: New Therapies in Cerebellar Disorders. Current neuropharmacology 17 (1):7-13. do:10.2174 / 1570159x16666180905093535

[0152] All features described herein (including any claim, brief description and accompanying drawings) and / or all steps of any method described, may be combined with any of the above aspects in any combination, except for combinations where at least some of the features and / or steps are mutually exclusive.

[0153] It should be understood that the above modalities and examples are not intended to be limiting in any aspect of the scope of the description and that the claims presented herein are intended to encompass all modalities and examples, whether or not explicitly presented herein.

[0154] All patents, patent applications and publications cited herein are incorporated by reference in their entirety.

Claims

CLAIMS 1. A method of treating ataxia in a subject in need thereof, the method comprising administering a combination of a therapeutically effective amount of acetyl-leucine and (i) a therapeutically effective amount of 4-aminopyridine or (ii) a therapeutically effective amount of acetazolamide to the subject.

2. The method of claim 1, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered simultaneously.

3. The method of claim 2, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered as a single pharmaceutical formulation.

4. The method of claim 2, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered as two separate pharmaceutical formulations.

5. The method of claim 1, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered sequentially.

6. The method of claim 5, wherein acetyl-leucine is administered before 4-aminopyridine or acetazolamide.

7. The method of claim 5, wherein acetyl-leucine is administered after 4-aminopyridine or acetazolamide.

8. The method of any of claims 5-7, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered from approximately 1 minute to approximately 6 hours apart.

9. The method of claim 8, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered approximately 1 minute to 3 hours apart.

10. The method of claim 9, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered approximately 1 minute to 1 hour apart.

11. The method of any of claims 1-10, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered orally.

12. The method of any of claims 1-11, wherein acetyl-leucine is administered once, twice or three times per day.

13. The method of any of claims 1-12, wherein 4-aminopyridine or acetazolamide is administered once, twice, or three times per day.

14. The method of any of claims 1-13, wherein approximately 3 g to approximately 15 g of acetyl-leucine are administered per day.

15. The method of any of claims 1-14, wherein approximately 10 mg to approximately 30 mg of 4-aminopyridine or approximately 500 mg to approximately 1000 mg of acetazolamide are administered per day.

16. The method of any of claims 1-15, wherein acetyl-leucine and 4-aminopyridine or acetazolamide are administered as first-line therapy for treating episodic ataxia.

17. The method of any of claims 1-16, wherein the ataxia is episodic ataxia. QQhb ΙΠ / 7 7Π7 / Β / YΙΛΙ 18. The method of any of claims 1-17, wherein episodic ataxia is episodic ataxia type 2.

19. The method of any of claims 1-18, wherein acetyl-leucine is administered in combination with 4-aminopyridine to the subject.

20. The method of any of claims 1-18, wherein acetyl-leucine is administered in combination 5 with acetazolamide to the subject.

21. The method of any of claims 1-20, wherein the acetyl-leucine is N-acetyl-DL-leucine.

22. The method of any of claims 1-20, wherein the acetyl-leucine is N-acetyl-L-leucine.

23. The method of any of claims 1-22, wherein the subject has a cytosine and thymidine deletion at position 2070-2071 in exon 16 of the CACNA1A gene. 10 24. A kit comprising acetyl-leucine and 4-aminopyridine or acetazolamide for treating ataxia in a subject.

25. The equipment of claim 24 further comprises instructions for administering acetyl-leucine and 4-aminopyridine or acetazolamide to the subject.

26. The equipment of claims 24 or 25, wherein the ataxia is episodic ataxia type 2.