WO2015026708A2

WO2015026708A2 - Amelioration of the effects of friedriech's ataxia

Info

Publication number: WO2015026708A2
Application number: PCT/US2014/051454
Authority: WO
Inventors: Robert B. Wilson; M. Grazia COTTICELLI; Andrew M. CRABBE
Original assignee: Wilson Robert B; Cotticelli M Grazia; Crabbe Andrew M
Priority date: 2013-08-20
Filing date: 2014-08-18
Publication date: 2015-02-26
Also published as: WO2015026708A3

Abstract

The effects of Friedreich's Ataxia are ameliorated by administering to a patient known or suspected of having the disease with essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom. Dosage regimes and kits are also featured.

Description

AMELIORATION OF THE EFFECTS OF FRIEDREICH'S ATAXIA

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent Application Serial No.

61/867,727, filed August 20, 2013, the contents of which are incorporated by reference herein for all purposes.

TECHNICAL FIELD

[0002] The present invention relates to the treatment of Friedreich's Ataxia.

BACKGROUND

[0003] The present invention is directed to amelioration of the effects of Friedreich's Ataxia. Friedreich's ataxia (FA) is an inherited, severe, and progressive neuro- and cardio- degenerative disorder for which there currently is no approved therapy. FA is the most common hereditary ataxia, and is caused by the decreased expression and/or function of frataxin, a mitochondrial matrix protein that binds iron and is involved in the formation of iron-sulfur- clusters (ISCs). Decreased frataxin function leads to decreased ISC formation, mitochondrial iron accumulation, cytosolic iron depletion, oxidative stress, and mitochondrial dysfunction.

[0004] Two compounds are being evaluated in phase II and phase III trials,

respectively, in FA patients. Pioglitazone, a known PGC1 alpha activator is in a clinical trial in France for FA. However, it suffers from obvious liabilities, which limit the dosages that can be tested in vivo. These liabilities include an increased risk of congestive heart failure, and that a compound with a very similar structure, Rosiglitazone, now carries a black box warning from the FDA for an increased risk of heart attacks. Given that cardiomyopathy is a prominent component of FA, Pioglitazone is not an attractive treatment for FA. Potent, relatively non-toxic drugs with desirable pharmaceutical properties are critically needed for the treatment of FA.

SUMMARY OF THE INVENTION

[0005] It has now been discovered that certain essentially free cis Δ9 fatty acids confer a significant amelioration of the effects of Friedreich's ataxia in patients. In this context, "amelioration" means improvements in disease-relevant biochemical measures in the cells of patients. Such improvements are believed to likely confer clinically significant therapeutic benefits to patients suffering from FA. Exemplary clinical disease effects which are expected to be reduced by administration of the free cis Δ9 fatty acids of the invention include hypertrophic cardiomyopathy, as evidenced by decreased hypertrophy and improved ejection fraction; ataxia, as evidenced by improvement in walking ability and fine motor coordination; insulin resistance, as evidenced by improved glucose handling; and vision, as evidenced by improved low-contrast vision testing.

[0006] At the same time, administration of the free cis Δ9 fatty acids of the invention to patients is unlikely to give rise to some or all of the medically contraindicated effects in patients which have been reported for Pioglitazone, especially an increased risk of congestive heart failure.

[0007] The free fatty acids useful in the practice of this invention are those cis Δ9 fatty acid molecules which have from 12 to 24 carbon atoms together with a cis double bond at the C9 carbon atom. The preferred cis Δ9 fatty acids are oleic, palmitoleic, myristoleic and gadoleic acids. Any single one of these cis Δ9 fatty acids may be employed as may combinations of cis Δ9 fatty acids. Further, different cis Δ9 fatty acids or fatty acid combinations may be employed over time or on a repetitive basis.

[0008] The fatty acids preferred for use in the present invention are "essentially free." By this is meant that these are generally provided with the acid moiety unreacted in ester, amide or similar forms such as is found in glycerides, for example. As will be appreciated, nearly all natural products, e.g. olive oil, contains fatty acids, including certain Δ9 fatty acids, however these are nearly completely found in ester form in glycerides. It will be appreciated that some degree of esterification of other modification may be found in the "essential free" fatty acids without departing from the spirit of the invention, however it is preferred that such modification be maintained at a low level. The level of ester or other modification which is acceptable will largely depend upon the cis Δ9 fatty acid employed, the route of administration, and other practicalities, but overall, that level is preferred to be less than 5 mol percent. It is even more preferred that the level of modification be less than 1 mole percent.

[0009] The present invention is directed to the use of essentially free cis Δ9 fatty acids having particular numbers of carbon atoms for FA therapeutics. It is to be understood that compounds within the invention may contain different fatty acids, such as trans fatty acids, fatty acids with different numbers of carbon atoms, fatty acids in esterified molecules and, indeed, other compositions both natural and synthetic. Essentially free is intended to define the efficacious compounds useful in the compositions of the invention so that the presence of these molecules may be determined for purposes of determining the practice of the invention. The presence of other, even related, compounds may be ignored so long as they are not toxic and do not interfere with the therapeutic efficacy of the desired compounds of the invention.

[0010] The essentially free cis Δ9 fatty acids are preferably administered to patients having or suspected of having FA orally. Other routes of administration may be employed, however. These include, but are not limited to other enteral administrations; parenteral administration, such as intravenous, intra-arterial, intra-muscular, sub-cutaneous, or intrathecal; and topical administration. The amount of essentially free cis Δ9 fatty acid administered may vary with the route of administration. In general, for oral delivery, it is preferred that from about 30 mg to about 50 grams of free cis Δ9 fatty acid be given to a patient during a twenty- four hour period. It is more preferred that amounts of from 1 to about 10 grams be provided. In some applications, intrathecal delivery of essentially free cis Δ9 fatty acids may be preferred. If delivery is intrathecal, much lower dosages may be employed as compared to oral and other regimes. For intrathecal delivery, dosages as low as 300 ng could be used. Accordingly, for intrathecal delivery, amounts of from 300 ng to 30 mg may be employed with 500 ng to 20 mg being preferred.

[0011] While the material may be administered in a single bolus or instilled via a single drip, in some cases, multiple doses per day may be preferred. It may be advantageous to administer the therapeutic material two, three or four times daily.

[0012] The essentially free cis Δ9 fatty acids of the invention are conveniently administered to a patient in a pharmaceutically acceptable carrier or diluent. Any

pharmaceutically acceptable carrier may be employed in which the fatty acids of the invention either dissolves or may be suspended. Micellular formulations and formulations including microencapsulations or other phase restrictive constructs may find utility in this invention as may other customary formulations for oleaginous materials. It may also be desirable to include one or more surface active agents, viscosity modifiers or other adjuvants with materials for administration to patients to improve the pharmacodynamics, pharmacokinetics or both of the materials. Surfactants and other pharmaceutically acceptable adjuvants are known per se to pharmaceutical chemists and selection of useful molecules to stabilize and enhance the therapeutic materials of this invention is well within the routine skill of persons skilled in the pharmaceutical arts.

[0013] In some therapeutic regimes, patients are treated with the therapeutic compositions of this invention on an acute basis. In other regimes, chronic treatment is accomplished. It may be advantageous to monitor the state of amelioration of FA in a patient in treatment and to alter the identity of fatty acid or fatty acid combination, dosage and/or dosage timing or regime in response to that monitoring.

[0014] The cis Δ9 fatty acid compositions of this invention may include or may be coadministered with other pharmaceuticals or nutritive materials to improve the therapeutic efficacy of the treatment regime. For example, free cis Δ9 fatty acid therapeutic compositions may be co-administered with Pioglitazone in sub-acute amounts to provide therapeutic efficacy without the increased risk of congestive heart failure or other toxic effects found with larger amounts of the prior drug.

[0015] The compositions of the invention are preferably provided in containers, especially unit doses, to facilitate administration. It is preferred for certain embodiments that pluralities of such containers containing the materials of the invention be associated into kits for ease of distribution. Such containers or kits may comprise ampoules, vials, bottles or other enclosures with contain preselected amounts of therapeutic composition. Further, subdoses may be supplied for convenience in dosing different amounts of therapeutic material. These may be kitted with other articles, such as solvent, diluent and/or adjuvant materials, preferably in premeasured amounts. Such kits may also include IV or other administration paraphernalia, instructions, monitoring forms and other articles useful for acute or chronic administration of the therapeutic compositions of this invention.

[0016] The compositions of this invention are essentially natural and are well tolerated by the body. They are well absorbed and are, thus, rapidly available for therapeutics. They are non-toxic to reasonably high levels, are eliminated conventionally and are non-polluting. They are also quite stable. [0017] It is surprising that therapeutic compositions for FA may be provided employing essentially free cis Δ9 fatty acids of this invention. The biochemical hallmarks of the disorder are mitochondrial iron accumulation, and consequent oxidative stress. There is no obvious reason why essentially free cis Δ9 fatty acids should ameliorate these defects. Furthermore, in screening assays using primary FA fibroblasts from patients, or mouse fibroblasts expressing only human frataxin with a disease-associated point mutation (I154F), unsaturated fatty acids such as linoleic acid and alpha-lineoleic acid are toxic to the cells when the cells are stressed with iron and oxidant, whereas unsaturated fatty acids such as stearic acid are not (see Examples, below). This is because the double bonds in the unsaturated fatty acids provide a substrate for lipid peroxidation. The essential free cis Δ9 fatty acids described herein are unsaturated, hence the expectation was that they would also be toxic to the same cells stressed with iron and oxidant. Not only are the essential free cis Δ9 fatty acids non-toxic, which would have been a surprise in and of itself, but they actively rescue the cells from iron and oxidant concentrations that are lethal to the vast majority of the cells (see Examples, below).

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The present application is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the subject matter, there are shown in the drawings exemplary embodiments of the subject matter; however, the presently disclosed subject matter is not limited to the specific methods, processes, devices, and systems disclosed. In addition, the drawings are not necessarily drawn to scale. In the drawings:

[0019] FIG. 1 provides the chemical structure of oleic acid.

[0020] FIG. 2 illustrates Oleic Acid is protective in the iron-BSO model. The data shown are the mean and the standard deviation calculated from six independent replicates. NT, Not Treated; CC, Carrier Control; IDB, Idebenone (an antioxidant in a Phase III trial for FA in Europe); stearic, stearic acid; oleic, oleic acid; Lin, lineoleic acid; FAC, ferric ammonium citrate; BSO, L-bothionine (S,R)-sulfoxime.

[0021] FIG. 3 provides a dose Response of Oleic Acid (OA) in the iron-BSO model, as described herein. [0022] FIG. 4 shows the relative expression of PGC-1 alpha in human FA fibroblasts (GM3816) treated with Carrier Control (Ctrl), Pioglitazone (Pio; 10 microM) or Oleic acid (Oleic; 16 microM) for 96h, using quantitative, real-time PCR.

[0023] FIG. 5 shows Gadoleic Acid (GA) and Palmitoleic Acid (POA) are protective in the iron-BSO model. The data shown are the mean and the standard deviation calculated from six independent replicates. NT, Not Treated; CC, Carrier Control; OA, Oleic Acid; POA,

Palmitoleic Acid; GA, Gadoleic Acid; Idb, Idenenone; FAC, ferric ammonium citrate; BSO, L- bothionine (S,R)-sulfoxime.

[0024] FIG. 6 shows dose response protective effects of Gadoleic Acid (GA) and Palmitoleic Acid (POA) in the iron-BSO model. The data shown are the mean and the standard deviation calculated from six independent replicates. NT, Not Treated; CC, Carrier Control; POA, Palmitoleic Acid; OA, Oleic Acid; GA, Gadoleic Acid; Idb, Idenenone; FAC, ferric ammonium citrate; BSO, L-bothionine (S,R)-sulfoxime.

[0025] FIG. 7 shows that Olive and Safflower oils do not rescue FA cells, even at doses equivalent to 40 uM oleic acid. NT, Not Treated; CC, Carrier Control; OA, Oleic Acid; SF, Safflower; HOSF, High-Oleic Safflower; HLSF, High Linoleic Safflower; FAC, ferric ammonium citrate; BSO, L-bothionine (S,R)-sulfoxime.

[0026] FIG. 8 shows that the tri-glyceride of oleic acid (glyceryl-3 oleate) does not rescue FA cells. NT, Not Treated; CC, Carrier Control; OA, Oleic Acid; EtOH, ethanol (carrier); FAC, ferric ammonium citrate; BSO, L-bothionine (S,R)-sulfoxime.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0027] The present invention is directed to amelioration of the effects of Friedreich's Ataxia. Friedreich's ataxia (FA) is an inherited, severe, and progressive neuro- and cardio- degenerative disorder for which there currently is no approved therapy. Certain embodiments provide methods for ameliorating the effects of Friedreich's Ataxia in a patient known or suspected of having the disease comprising administering to the patient a therapeutically effective amount of at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

[0028] The present invention may be understood more readily by reference to the following description taken in connection with the accompanying Figures and Examples, all of which form a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, processes, conditions or parameters described or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless specifically otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement. Throughout this specification, claims, and drawings, it is recognized that the descriptions refer to compositions and processes of making and using said compositions. That is, where the disclosure describes or claims a feature or embodiment associated with a composition or a method of making or using a composition, it is appreciated that such a description or claim is intended to extend these features or embodiment to

embodiments in each of these contexts (i.e., compositions, methods of making, and methods of using).

[0029] In the present disclosure the singular forms "a," "an," and "the" include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a material" is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0030] When a value is expressed as an approximation by use of the descriptor "about," it will be understood that the particular value forms another embodiment. In general, use of the term "about" indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word "about." In other cases, the gradations used in a series of values may be used to determine the intended range available to the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range. [0031] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

[0032] The transitional terms "comprising," "consisting essentially of," and

"consisting" are intended to connote their generally in accepted meanings in the patent vernacular; that is, (i) "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method or process steps; (ii) "consisting of excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. Embodiments described in terms of the phrase "comprising" (or its equivalents), also provide, as embodiments, those which are independently described in terms of "consisting of and "consisting essentially of."

[0033] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" is to be interpreted as including the embodiments, "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0034] As described above, certain embodiments provide methods for ameliorating the effects of Friedreich's Ataxia in a patient known or suspected of having the disease comprising administering to the patient a therapeutically effective amount of at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

[0035] As used herein, unless otherwise stated, "at least one essentially free cis Δ9 fatty acid" describes a fatty acid that is, as much as practicably possible, is free of corresponding ester moieties. In related embodiments, the fatty acid is at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or essentially 100% by mol in the free fatty acid form, relative to the total content of the same fatty acid.

[0036] In some embodiments, this treatment is administered chronically. Unless otherwise stated, chronically may be defined in terms of a time period that reflects the total time the condition is to be ameliorated. In some cases, this may refer to times in eacess of 1, 3, 6, or 9 months, in excess of 1, 3, 6, 9, 12, or 24 years, or longer. Alternatively, or additionally, the at least one essentially free cis Δ9 fatty acid may be administered one, two, three, of four times daily, preferably up to four time daily.

[0037] As described above, the dosage is described as a therapeutically effective amount. While such an amount depends on the size of the patient, the mode of delivery, and the degree of control required, in certain embodiments, the therapeutically effective amount is an amount in a range of from 30 mg to 50 grams per day. In certain other embodiments, the amount is in a range bounded at the lower end by a value of about 0.1 mg (100 ng), 0.3 mg (300 ng), 0.5 mg (500 ng), 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg and bounded at the upper end by a value of about 100 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10 mg. In some embodiments, the therapeutically effective amount for intrathecal delivery, may be in a range of from about 300 ng to 30 mg.

[0038] In some embodiments, the at least one essentially free cis Δ9 fatty acid is oleic acid. In other embodiments, the at least one essentially free cis Δ9 fatty acid is palmitoleic acid. In still other embodiments, the at least one essentially free cis Δ9 fatty acid is myristoleic acid. In other embodiments, the at least one essentially free cis Δ9 fatty acid is gadoleic acid. These essentially free cis Δ9 fatty acid may be administered individually or in combination with one another. For example, in certain embodiments of the invention provide that the composition to be administered such that the at least one essentially free cis Δ9 fatty acid is a blend having a molar ratio in a ragne of from 10:90 to 90: 10 of oleic acid and at least one other essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis

configuration at the C9 carbon atom. In other embodiments, the ratio of oleic acid and another essentially free cis Δ9 fatty acid may in a range bounded at the lower end by a value of 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30 and at the upper end by 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, or 30:70. Additional exemplary ranges include 90: 10 to 80:20, 80:20 to 70:30, 70:30 to 60:40, 60:40 to 50:50, 50:50 to 40:60, 40:60 to 30:70, 30:70 to 20:80, 20:80 to 10:90, or any combination thereof.

[0039] The at least one essentially free cis Δ9 fatty acid may be packaged as a unit therapeutic dosage having said essentially free cis Δ9 fatty acid in an amount of 30 mg to 50 grams per day. This amount is a suitable daily dosage for an average adult human patient (e.g., 50-100 kg), on a mg/kg basis. It will be understood that the pharmaceutical formulations of the present invention need not necessarily contain the entire amount of the agent that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of doses of such pharmaceutical formulations. That is, the unit dose form may provide amounts of said essentially free cis Δ9 fatty acid in amounts consistent with the anticipated dosage administration regimen. That is, in some embodiments, the unit dosage form may comprise an amount in a range of from about 0.1 mg (100 ng) to about 0.3 mg, from about 0.3 mg (300 ng) to about 0.5 mg (500 ng), from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 20 mg, from about 20 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, or a combination thereof. The unit dosage form may further comprise at least one therapeutically acceptable carrier, container, diluent, flavorant or binder.

[0040] Suitable dosage forms include but are not limited to oral, sub-lingual, mucosal, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intraarterial, sub-arachinoid, bronchial, lymphatic, and intrauterine administration, and other dosage forms for systemic delivery of active ingredients. In preferred embodiments, the dosage form is suitable for oral or intrathecal, administration.

[0041] To prepare such pharmaceutical dosage forms, at least one essentially free cis Δ9 fatty acid is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.

[0042] For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.

[0043] In preparing the compositions in oral dosage form, any of the usual

pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules, caplets, and tablets, suitable carriers and additives include starches sugars diluents granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.

[0044] Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules.

Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.

[0045] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.

[0046] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory

ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a poly hydroxy alcohol, for example glycerol or sorbitol.

[0047] Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unitdose or multi-dose form.

[0048] Parenteral administration may comprise any suitable form of systemic delivery or delivery directly to the CNS. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.

[0049] In addition to the aforementioned ingredients, formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants,

preservatives (including antioxidants), and the like. Such pharmaceutical compositions can be prepared by methods and contain carriers which are well-known in the art. A generally recognized compendium of such methods and ingredients is Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippingcott Williams and Wilkins: Philadelphia, Pa., 2000.

[0050] The formulation of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.

[0051] In a preferred embodiment of the present invention, the compounds are formulated in capsules or tablets.

[0052] A pharmaceutical composition for intrathecal administration may contain from about 0.01% to about 100% by weight of the active agents of the present invention, based upon 100% weight of total pharmaceutical composition.

[0053] The invention also contemplates pharmaceutically acceptable packages containing at least one unit, including a plurality of, therapeutic dosage forms in accordance with any of of the preceding compositions. In some embodiments, these kits further comprise instructions for the administration (dosages, timings, etc) of these therapeutical dosage forms. Where the unit therapeutic dosage form is adapted for intrathecal administration, it may contain essentially free cis Δ9 fatty acid in a range of from about 300 ng to 30 mg. [0054] The following embodiments are intended to complement, rather than supplant, those embodiments already described.

[0055] Embodiment 1. A method for ameliorating the effects of Friedreich's Ataxia in a patient known or suspected of having the disease comprising administering to the patient a therapeutically effective amount of at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

[0056] Embodiment 2. The method of Embodiment 1, wherein the at least one essentially free cis Δ9 fatty acid is administered chronically.

[0057] Embodiment 3. The method of Embodiment 1 or 2, wherein the at least one essentially free cis Δ9 fatty acid is administered up to four times daily.

[0058] Embodiment 4. The method of any one of Embodiments 1 to 3, wherein the therapeutically effective amount is from 30 mg to 50 grams per day.

[0059] Embodiment 5. The method of Embodiment 1 or 2, wherein the therapeutically effective amount for intrathecal delivery, and the amount is from 300 ng to 30 mg.

[0060] Embodiment 6. The method of any one of Embodiments 1 to 5, wherein the at least one essentially free cis Δ9 fatty acid is oleic acid.

[0061] Embodiment 7. The method of any one of Embodiments 1 to 5, wherein the at least one essentially free cis Δ9 fatty acid is palmitoleic acid.

[0062] Embodiment 8. The method of any one of Embodiments 1 to 5, wherein the at least one essentially free cis Δ9 fatty acid is myristoleic acid.

[0063] Embodiment 9. The method of any one of Embodiments 1 to 5, wherein the at least one essentially free cis Δ9 fatty acid is gadoleic acid.

[0064] Embodiment 10. The method of any one of Embodiments 1 to 9, wherein the at least one essentially free cis Δ9 fatty acid is a blend having a molar ratio of from 10:90 to 90: 10 of oleic acid and at least one other essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

[0065] Embodiment 11. A unit therapeutic dosage form comprising at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom optionally combined with a therapeutically acceptable excipient (carrier, container, diluent, flavorant or binder). [0066] Embodiment 12. The unit therapeutic dosage form of Embodiment 11, wherein the therapeutically effective amount is from 30 mg to 50 grams per day.

[0067] Embodiment 13. The unit therapeutic dosage form of Embodiment 11 or 12, wherein the therapeutically effective amount for intrathecal delivery, and the amount is from 300 ng to 30 mg.

[0068] Embodiment 14. The unit therapeutic dosage form of any one of Embodiments 11 to 13, wherein the at least one essentially free cis Δ9 fatty acid is oleic acid.

[0069] Embodiment 15. The unit therapeutic dosage form of any one of Embodiments 11 to 13, wherein the at least one essentially free cis Δ9 fatty acid is palmitoleic acid.

[0070] Embodiment 16. The unit therapeutic dosage form of any one of Embodiments 11 to 13, wherein the at least one essentially free cis Δ9 fatty acid is myristoleic acid.

[0071] Embodiment 17. The unit therapeutic dosage form of any one of Embodiments 11 to 13, wherein the at least one essentially free cis Δ9 fatty acid is gadoleic acid.

[0072] Embodiment 18. The unit therapeutic dosage form of any one of Embodiments 11 to 17, wherein the at least one essentially free cis Δ9 fatty acid is a blend having a molar ratio of from 10:90 to 90: 10 of oleic acid and at least one other essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

[0073] Embodiment 19. The unit therapeutic dosage form of any one of Embodiments 11 to 18, wherein the dose is comprised of a plurality of subdoses.

[0074] Embodiment 20. A kit for treatment of disease comprising a plurality of unit therapeutic dosage forms in accordance with any one of Embodiments 11 to 19.

[0075] Embodiment 21. The use of at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom for the treatment of Friedreich's Ataxia.

[0076] Embodiment 22. The use of Embodiment 21, wherein the at least one essentially free cis Δ9 fatty acid is oleic acid.

[0077] Embodiment 23. The use of Embodiment 21 , wherein the at least one essentially free cis Δ9 fatty acid is palmitoleic acid. [0078] Embodiment 24. The use of Embodiment 21, wherein the at least one essentially free cis Δ9 fatty acid is myristoleic acid.

[0079] Embodiment 25. The use of Embodiment 21 , wherein the at least one essentially free cis Δ9 fatty acid is gadoleic acid.

EXAMPLES

[0080] The following Examples are provided to illustrate some of the concepts described within this disclosure. While each Example is considered to provide specific individual embodiments of the methods using the device, none of the Examples should be considered to limit the more general embodiments described herein.

[0081] The present inventors have developed an assay for FA using primary FA fibroblasts from patients, or mouse fibroblasts expressing only human frataxin with a disease- associated point mutation (I154F). Cotticelli MG, Rasmussen L, Kushner NL, et al. Primary and Secondary Drug Screening Assays for Friedreich Ataxia. J Biomol Screen 17, 303-13 (2012). This publication is incorporated herein by reference. It was found that the fibroblasts are sensitive to low levels of ferric ammonium citrate (FAC) and L-bothionine (S,R)-sulfoxime (BSO), a compound that inhibits glutathione synthesis. In combination, FAC plus BSO causes synergist lethality to FA cells in culture. This is referred to as the "iron-BSO" model. Using this assay, it was surprisingly discovered that essentially free oleic acid protects FA cells from concentrations of FAC and BSO otherwise lethal to FA cells in culture. This assay was repeated several times yielding the same remarkable result (FIG. 2 and 3).

[0082] FA is unusual among genetic disorders in that the exonic sequences are intact in most disease alleles, which harbor a trinucleotide repeat expansion in the first intron of the gene encoding frataxin, thereby decreasing its expression. Microarray experiments using cells from FA patients have repeatedly demonstrated a paradoxical decrease in PGC1 alpha, a transcriptional co-activator that positively regulates the expression of genes involved in mitochondrial biogenesis, oxidative stress response, and frataxin expression itself. It has been hypothesized that the paradoxical decrease in PGC1 alpha (secondary, perhaps, to the low cytosolic iron in FA cells) contributes to the decrease in frataxin expression that underlies the disorder in most cases. Using quantitative RT-PCR, the inventors tested whether oleic acid increases PGC1 alpha expression. Using Pioglitazone, a known activator of PGC1 alpha as a positive control, they found repeatedly that oleic acid induces a statistically significant increase in PGC1 alpha expression (FIG. 4).

[0083] In order to establish a connection between the chemical structure of oleic acid and its ability to protect FA cells treated with iron and BSO, the inventors tested whether other delta-9 fatty acids also have protective abilities. It was found that two other delta-9 fatty acids, gadoleic (20 carbons total) and palmitoleic (16 carbons total) are also protective, with gadoleic acid showing a slightly higher potency than oleic acid, and palmitoleic acid showing a lower potency (FIGs. 5 and 6).

[0084] Oleic acid may also be esterified into a tri- or di-glyceride, however these forms are not useful in the practice of this invention. The inventors were surprised to find that the protective effects of essentially free oleic acid are not shared by the esterified counterparts. Safflower oil and olive oil contain oleic acid esterified as triglycerides. When FA cells in the iron-BSO model were treated with safflower oil and olive oil, no significant protective effects were observed, even at doses equivalent to 40 uM oleic acid (FIGs. 7 and 8). Purified oleic acid tri-glyceride (glyceryl-3 oleate) was similarly unable to protect (FIG. 8).

[0085] As those skilled in the art will appreciate, numerous modifications and variations of the present invention are possible in light of these teachings, and all such are contemplated hereby. For example, in addition to the embodiments described herein, the present invention contemplates and claims those inventions resulting from the combination of features of the invention cited herein and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.

[0086] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.

Claims

What is claimed is:

1. A method for ameliorating the effects of Friedreich's Ataxia in a patient known or suspected of having the disease comprising administering to the patient a therapeutically effective amount of at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom.

2. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is administered chronically.

3. The method of claim 2 wherein the at least one essentially free cis Δ9 fatty acid is administered up to four times daily.

4. The method of claim 2 wherein the therapeutically effective amount is from 30 mg to 50 grams per day.

5. The method of claim 2 wherein the therapeutically effective amount for intrathecal delivery, and the amount is from 300 ng to 30 mg.

6. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is oleic acid.

7. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is palmitoleic acid.

8. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is myristoleic acid.

9. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is gadoleic acid.

10. The method of claim 1 wherein the at least one essentially free cis Δ9 fatty acid is a blend having a molar ratio of from 10:90 to 90: 10 of oleic acid and at least one other essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom

11. A unit therapeutic dosage form comprising at least one essentially free cis Δ9 fatty acid having from 12 to 24 carbon atoms and a single double bond in a cis configuration at the C9 carbon atom optionally combined with a therapeutically acceptable carrier, container, diluent, flavorant or binder.

12. The unit therapeutic dosage form of claim 11 wherein the dose is comprised of a plurality of subdoses.

13. The unit therapeutic dosage form of claim 11 containing from 30 mg to 50 grams per day of said essentially free cis Δ9 fatty acid.

14. The unit therapeutic dosage form of claim 11 adapted for intrathecal administration and containing from 300 ng to 30 mg of said essentially free cis Δ9 fatty acid.

15. A kit for treatment of disease comprising a plurality of unit therapeutic dosage forms in accordance with any of claims 11, 12, 13 or 14.