Use of ebselen or one of its derivatives for treating mitochondrial pathologies or dysfunctions

Abstract

The present invention relates to the use of one of ebselen or a derivative thereof for treating mitochondrial pathologies or dysfunctions associated with mitochondrial symptoms or dysfunctions, in particular deficiencies in complex I.

Description

Technical Field

[0001] The present invention aims to provide a novel pharmacological tool for treating conditions associated with mitochondrial disease or dysfunction, particularly mitochondrial complex I deficiency.

Background Art

[0002] Mitochondrial diseases are frequent metabolic disorders characterized by high clinical and genetic heterogeneity, revealed by the fact that mitochondria fail to produce sufficient energy for the proper functioning of the organism. Mitochondrial diseases can be present at birth, but can occur at any age. At the genetic level, mitochondria have their own DNA (or mitochondrial DNA), but most mitochondrial proteins are characterized by their dependence on the nuclear genome. Therefore, genetic abnormalities harbored by the mitochondrial and nuclear genomes are the cause of high mitochondrial diseases and reflect very high clinical and genetic heterogeneity. It is estimated that 1 in 4,300 people suffer from mitochondrial disease (Gorman et al., 2015, Ann Neurol. 77(5):753-9).

[0003] Mitochondrial diseases can affect almost all parts of the body, particularly cells in the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. The symptoms of mitochondrial disease vary depending on the organ involved and preferably affect tissues that are high energy consumers such as muscle, brain and heart. The symptoms in patients can be moderate to severe with respect to one or more organs.

[0004] The symptoms of mitochondrial disease are - inadequate growth - muscle weakness, muscle pain, insufficient muscle tone, intolerance to exertion - visual and / or hearing impairments - learning disabilities, onset of delay, mental retardation, - autism or autistic features - Heart failure, cardiac arrhythmia or abnormal cardiac conduction, - Liver or kidney disease, - Gastrointestinal disorders, dysphagia, dyschezia or constipation, unexplained vomiting, abdominal pain, gastrointestinal reflux, - Diabetes, - Increased risk of infection, - Neuropathy, epileptic seizures, migraine, occurrence of cerebrovascular disorders (attacks) - Movement disorders, - Hypofunction of the thyroid and / or adrenal glands, - Respiratory disorders, - Lactic acidosis, i.e., accumulation of lactic acid in the blood or urine, - Dementia may be mentioned.

[0005] Mitochondrial dysfunction can occur in some cases due to another disease or another disorder when the mitochondria do not function properly. A number of pathological conditions can cause secondary mitochondrial dysfunction, especially Alzheimer's or Parkinson's disease, muscular dystrophy, Lou Gehrig's disease, diabetes and cancer. People suffering from secondary mitochondrial dysfunction do not have a primary mitochondrial disease of genetic origin but have similar symptoms. Furthermore, certain drugs can target or damage the mitochondria.

[0006] Mitochondrial complex I deficiency is the most common defect observed in more than 30% of mitochondrial diseases. Among these, the two most frequently occurring clinical phenotypes associated with complex I deficiency are Leigh syndrome, which is often a lethal or more moderate phenotype such as Leber hereditary optic neuropathy (LHOL). MELAS syndrome is also a common mitochondrial disease caused by mutations in the mitochondrial genome and is associated with a severe decrease in mitochondrial complex I activity.

[0007] Complex I is composed of at least 44 subunits, of which 7, namely ND1 - 6 and ND4L, are encoded by mitochondrial genes, while the others are encoded by nuclear genes. As a result, the clinical and molecular features associated with hereditary Complex I deficiency are highly diverse. Among the subunits of Complex I, mutations targeting the gene NDUFV1 have been shown to be responsible for severe neurological phenotypes (Schuelke et al., 1999, Nat Genet. 21(3):260 - 61). Mutations affecting the subunit NDUFS8 are associated with Leigh syndrome (Procaccio et al., 2004, Neurology 62:1899), and mutations targeting the subunit ND3 encoded by mitochondrial DNA have been reported in Leigh syndrome and LHON (Sarzi et al., 2007 American Journal of Medical Genetics 143:33 - 41, Wang et al., 2009, Neurogenetics. 10:337 - 345). Furthermore, mutations affecting the subunit ND6 encoded by mitochondrial DNA have been reported in LHON (Johns et al., 1992, Biochem Biophys Res Commun. 187(3):1551 - 7).

[0008] Furthermore, Complex I deficiency has been identified as a secondary mitochondrial dysfunction associated with age - related neurodegenerative diseases such as Parkinson's disease.

[0009] Even though most mitochondrial diseases have a genetic origin, gene therapy seems difficult to implement due to genetic and clinical diversity and the complexity of these diseases.

[0010] The aim of current treatment is, for example, the following recommendations: - The use of vitamin therapy, - Energy conversion, - Delay of activity, - Maintaining the environment at room temperature, Protection against exposure to concurrent diseases (infections, stress), - maintaining nutrition and adequate hydration, to relieve symptoms and delay the progression of disease or dysfunction.

[0011] It should be noted that International Publication No. 2020 / 254632 and International Publication No. 2022 / 018297 have recently reported the treatment of these pathologies or deficiencies using disulfiram and alverine, respectively.

[0012] However, there is still a need to find new therapeutic and pharmacological approaches for treating these types of dysfunctions or diseases, based on causative and asymptomatic treatments.

[0013] International Publication No. 2014 / 150688 describes the treatment of cancer using molecules such as ebselen that can inhibit enzymes from mitochondrial complex (1-C), particularly the enzyme MTHFD2.

[0014] JIA ZHI-QIANG et al. (Neurosc. Letters, 2018, vol. 678, pp110-17) reported the beneficial effects of ebselen in treating acute spinal cord lesions, accompanied by neuroprotective effects and improvement of mitochondrial function.

[0015] ARAKAWA MOTOKI et al. (Cerebellum, 2007, 6(4), pp308-14) is related to neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, which are described as being associated with mitochondrial degeneration. This document focuses on the positive effect of NAC against toxicity induced by 4-hydroxynonenal (HNE) in neurons and mentions the neuroprotective effect of ebselen and its possible use in combination with NAC.

[0016] AZAD GAJENDRA et al. (Molecular Biology Reports, 2014, 41(8), pp4865 - 79) is a review specialized in ebselen, which is described as a promising antioxidant. Table 2 lists all the pathological conditions that can be improved by the administration of ebselen.

[0017] CAPPER MICHAEL et al. (Nature Communications, 2018, 9(1)) deals with the effect of ebselen on the enzyme superoxide dismutase 1 (SOD1), and its mutations can cause pathological conditions such as amyotrophic lateral sclerosis (ALS).

Prior Art Documents

Patent Documents

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Patent Document 1

Patent Document 2

Patent Document 3

Non - Patent Documents

[0019]

Non - Patent Document 1

Non - Patent Document 2

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Non - Patent Document 4

[0020] The present inventors have shown that ebselen, particularly drugs currently used in clinical trials for the treatment of hearing disorders such as Meniere's disease, and its derivatives such as etaselen, are effective in the context of the treatment of diseases associated with mitochondrial dysfunction, particularly diseases of the mitochondrial respiratory chain, and preferably diseases associated with complex I deficiency. Therefore, this research opens the way for the use of a new family of compounds in this context.

[0021] Definitions The following definitions provide the general meanings used within the framework of the present invention and must be considered unless another definition is explicitly indicated.

[0022] The terms "about," "approximately," "on the order of," and "substantially" as used herein to specify a measurable value such as an amount, time, and the like are to be understood to mean incorporating a variation of up to ±20%, or ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1% with respect to the specified value.

[0023] Throughout the entire disclosure and throughout the various aspects of the invention, intervals / ranges may be presented in the form of intervals of values (range format). It should be understood that the description of values in interval form is done for convenience only and should not be construed as limiting the scope of the invention. Consequently, the description of a range is to be considered as having all the possible sub-ranges specifically disclosed and the individual numerical values within the range. For example, a description of a range such as "1 to 6" is to be considered as having the specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6 etc., and the individual numbers within the range such as 1, 2, 2.7, 3, 4, 5, 5.3 and 6. This applies regardless of the degree of the range.

[0024] "Isolated" means extracted or removed from its environment or natural state. For example, an isolated nucleic acid or peptide is a nucleic acid or peptide that has been extracted from the natural environment in which they are normally found, whether or not they are present in, for example, a plant or a living animal. For example, a nucleic acid or peptide that naturally exists in a living animal is not an isolated nucleic acid or peptide in the sense of the present invention, while a similar nucleic acid or peptide that has been partially or completely separated from other components present in its natural environment is "isolated" per se within the scope of the meaning of the present invention. An isolated nucleic acid or peptide may exist in a substantially purified form or may exist in an unnatural environment such as, for example, a host cell.

[0025] When the term "abnormal" is used with respect to an organism, tissue, cell or their components, it refers to an organism, tissue, cell or their components in which at least one observable or detectable characteristic (e.g., age, treatment, time, etc.) of each of those organisms, tissues, cells or their components that exhibits "normal" (expected) characteristics is different. What is standard or expected for one type of cell or tissue may be abnormal for another cell or tissue.

[0026] The terms "patient", "subject", "individual" and other terms are used interchangeably herein and refer to an animal or its cells that can be subjected to the methods described herein, either in vitro or in situ. In certain non-limiting embodiments, the patient, subject or individual is an animal, preferably a mammal, more preferably a human, regardless of being male or female. The animal can also be a non-human primate (NHP) such as a mouse, rat, pig, dog or macaque.

[0027] Within the scope of the present invention, a "disease" or "pathological condition" is a health state of an animal that has an adverse effect on the homeostasis of the animal and will continue to deteriorate if the disease is not treated. On the other hand, within the scope of the present invention, a "disorder" or "dysfunction" is a health state in which the animal can maintain its homeostasis, but the health state of the animal is less preferable than it would be if the disorder did not exist. In the absence of treatment, the disorder does not necessarily lead to a worsening health state of the animal over time.

[0028] A disease or "disorder" is "attenuated" ("reduced") or "improved" if the severity of the symptoms of the disease or disorder, the frequency with which the symptoms are felt by the subject, or both, are reduced. The definition also includes the disappearance of the progression of the disease, i.e., the cessation of the progression of the disease or disorder. A disease or "disorder" is "cured" ("recovered") if the severity of the symptoms of the disease or disorder, the frequency with which the symptoms are felt by the patient, or both, are eliminated.

[0029] In the context of the present invention, a "therapeutic" treatment is a treatment applied to a subject having symptoms (signs) of a medical condition, where the goal is to reduce or eliminate the symptoms. In the framework of the present invention, "treatment of a disease or disorder" means a reduction in the frequency or severity of at least one sign or symptom of the disease or disorder felt by the subject. A treatment is said to be prophylactic when it is applied, in particular when the subject does not present, or does not yet present, symptoms of the disease and / or when the disease has not been diagnosed, to prevent its onset, spread or worsening.

[0030] As used herein, "treatment of a disease or disorder" means reducing the frequency or severity of at least one sign or symptom of the disease or disorder felt by the subject. Diseases or disorders are used interchangeably in the context of the treatment according to the present invention.

[0031] Within the meaning of the present invention, an "efficacious quantity" or "effective quantity" of a compound is the amount of the compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered. The expression "therapeutically effective amount" refers to an amount that is sufficient or effective to prevent or treat (in other terms, delay or prevent onset, prevent progression, inhibit, reduce, decrease or reverse) the disease or disorder, including alleviating the symptoms of the disease or disorder.

[0032] The present invention relates to a compound having the formula moiety: JPEG2025521872000001.jpg4347, or of the formula: JPEG2025521872000002.jpg2146, or of the formula: JPEG2025521872000003.jpg2047, wherein, E is O, S, SO (S=O), SO2 (O=S=O), Se or SeO (Se=O), each of phenyl rings A and B may optionally be substituted with one or more substituents, each substituent is - halogen, preferably halogen selected from F, Cl and Br, - alcohol, - amine, - nitro, - C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted with one or more halogen atoms preferably selected from F, Cl and Br, C1-C4 alkyl, and - C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted with one or more halogen atoms preferably selected from F, Cl and Br, C1-C4 alkoxy, independently selected from the group consisting of compounds, or relates to the use of a pharmaceutical composition containing said halogen.

[0033] In other terms, the present invention provides a formula moiety for treating diseases associated with mitochondrial dysfunction: a compound having JPEG2025521872000004.jpg4044, or a formula: a compound of JPEG2025521872000005.jpg2146, or a formula: a compound of JPEG2025521872000006.jpg2047, wherein in the formula, E is O, S, SO (S=O), SO2 (O=S=O), Se or SeO (Se=O), each of phenyl rings A and B may optionally be substituted with one or more substituents, each substituent is - halogen, preferably halogen selected from F, Cl and Br, - alcohol, - amine, - nitro, - C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted by one or more halogen atoms preferably selected from F, Cl, and Br, and - C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted by one or more halogen atoms preferably selected from F, Cl, and Br, a compound independently selected from or a pharmaceutical composition containing said halogen.

[0034] According to another aspect, the present invention relates to a method for treating a disease associated with mitochondrial dysfunction, and for treating a disease associated with mitochondrial dysfunction, a formula portion: a compound having JPEG2025521872000007.jpg4347, or a formula: a compound of JPEG2025521872000008.jpg2146, or a formula: a compound of JPEG2025521872000009.jpg2047, wherein in the formula, E is O, S, SO (S=O), SO2 (O=S=O), Se or SeO (Se=O), each of phenyl rings A and B may optionally be substituted by one or more substituents, each substituent is - halogen, preferably halogen selected from F, Cl, and Br, - alcohol, - amine, - nitro, -C1-C2 alkyl or C1-C4 alkyl such as C1 alkyl, each of which may optionally be substituted by one or more halogen atoms preferably selected from F, Cl, and Br, and -C1-C2 alkoxy or C1-C4 alkoxy such as C1 alkoxy, each of which may optionally be substituted by one or more halogen atoms preferably selected from F, Cl, and Br, a compound independently selected from among or a method comprising administration to a subject of the pharmaceutical composition containing the halogen.

[0035] The compounds implemented within the framework of the present invention can have the activity of inhibiting inositol monophosphatase (IMPase), and the activity can be tested as described by Singh et al. (Nat Commun. 2013;4:1332.doi:10.1038 / ncomms2320).

[0036] According to a specific embodiment, such a compound is not valproic acid or carbamazepine.

[0037] The compounds implemented within the framework of the present invention can have antioxidant activity, and the activity can be tested as described by Noguchi et al. (Biochem Pharmacol 1992;44:39-44) and Nakamura et al. (J Biol Chem.,2002;277(4):2687-94).

[0038] According to a specific embodiment, such a compound is not ascorbic acid.

[0039] According to a specific embodiment, the formula: The compound implemented within the framework of the present invention having the group of JPEG2025521872000010.jpg4347 is It is one of etaselen or its derivatives or analogs, as defined below.

[0040] Etaselen or BBSKE (CAS number: 217798-39-5) has the following formula. JPEG2025521872000011.jpg1731

[0041] A derivative or analog of etaselen is, for example, the chlorinated derivative MAD423 of the formula. JPEG2025521872000012.jpg2250

[0042] Therefore, the compound of interest in the framework of the present invention has the following formula: JPEG2025521872000013.jpg2047, where In the formula, E is O, S, SO, SO2, Se or SeO, and Each of phenyl rings A and B may optionally be substituted with one or more substituents, Each substituent is - a halogen selected from among - halogen, preferably F, Cl and Br, - an alcohol, - an amine, - nitro, - a C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted with one or more halogen atoms selected from among F, Cl and Br, and - a C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted with one or more halogen atoms selected from among F, Cl and Br, and is independently selected from among those having the formula.

[0043] According to another embodiment, the target compound implemented in the framework of the present invention is as described in WO 2012 / 107735 pamphlet, that is, a compound of formula I, or a pharmaceutically acceptable salt thereof, and formula I is the following formula: JPEG2025521872000014.jpg2146 and wherein E is O, S, SO, SO2, Se or SeO and each of the phenyl rings A and B may optionally be substituted with one or more substituents each substituent is - halogen, preferably halogen selected from F, Cl and Br - alcohol - amine - nitro - C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted with one or more halogen atoms preferably selected from F, Cl and Br, C1-C4 alkyl, and - C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted with one or more halogen atoms preferably selected from F, Cl and Br, C1-C4 alkoxy, and is independently selected from among them.

[0044] According to a preferred embodiment, such a compound is - 2-phenyl-1,2-benzisoselenazol-3(2H)-one or ebselen of the formula: JPEG2025521872000015.jpg2142- 2-phenyl-1,2-benzisoselenazol-3(2H)-one or ebselen sulfur (2-phenyl-2,3-dihydro-1,2-benzothiazol-3-one) of the formula: JPEG2025521872000016.jpg1944- 1-oxide-2-phenyl-1,2-benzisoselenazol-3(2H)-one or ebselen oxide (ebselen oxide) or ebselen selenoxide of the formula: JPEG2025521872000017.jpg 1725 - type: Ebselen - OH para 1 JPEG2025521872000018.jpg 2449 - type: Ebselen - OH ortho JPEG2025521872000019.jpg 5192 - type: Ebselen - OH para 2 JPEG2025521872000020.jpg 47111 - type: MAD281 (6 - methoxy - 2 - phenylbenzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000021.jpg 50120 - type: MAD309 (6 - hydroxy - 2 - phenylbenzo[d][1,2]selenazol - 3(2H) - one 1 - oxide) JPEG2025521872000022.jpg 60115 - type: MAD331 (6 - chloro - 2 - phenylbenzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000023.jpg 51115 - type: MAD332 (6 - fluoro - 2 - phenylbenzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000024.jpg 51113 - type: MAD349 (2 - (2,6 - dichlorophenylbenzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000025.jpg 5687 - type: MAD380 (2 - (3 - hydroxyphenylbenzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000026.jpg 46101 - type: MAD383 (6 - chloro - 2 - (3 - trifluoromethyl)phenyl)benzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000027.jpg 48121 - type: MAD384 (2 - (3 - nitrophenyl)benzo[d][1,2]selenazol - 3(2H) - one) JPEG2025521872000028.jpg 49111-form MAD385 (2-(3-difluoromethoxy)phenyl)benzo[d][1,2]selenazol-3(2H)-one: JPEG2025521872000029.jpg 47122-form MAD413 (6-chloro-2-phenylbenzo[d][1,2]selenazol-3(2H)-one 1-oxide): JPEG2025521872000030.jpg 59111-form MAD463 (6-fluoro-2-phenylbenzo[d][1,2]selenazol-3(2H)-one 1-oxide): JPEG2025521872000031.jpg 5395

[0045] Preferred compounds according to the present invention are ebselen and ebselen oxides, preferably their derivatives or analogs such as ebselen, as defined below.

[0046] Ebselen (2-phenyl-1,2-benzoselenazol-3(2H)-one, CAS number: 60940-34-3), also known as PZ51, DR3305 and SPI-1005, is a synthetic molecule that can mimic glutathione peroxidase. The therapeutic activities of this molecule have been described in relation to ischemic lesions, seizures, hearing impairment and bipolar disorder. It is also effective in treating Clostridioides difficile infections and exhibits bactericidal activity against Aspergillus fumigatus.

[0047] In fact, this molecule is the subject of a Phase III clinical trial for the treatment of Meniere's disease and hearing impairment. Ebselen is orally administered at different doses of 200 mg to 600 mg per day (in the form of 200 mg gel caps) for at least 21 days.

[0048] In a yeast model, in particular Saccharomyces cerevisiae, in a filamentous fungus, in particular Podospora anserina, in human cells, in particular in any of fibroblasts or myoblasts of a patient suffering from a disease state, these compounds having the same biological activity, namely those reported in the examples, in particular restoration of respiratory growth, restoration of cell respiration or mitochondrial ATP levels, in particular derivatives or analogs of ebselen, are also targeted by the present invention.

[0049] The term "derivative" (or "analog") includes derivatives and metabolites, as well as pharmaceutically acceptable salts. A derivative is a compound derived from another (typically a precursor having a similar chemical structure) after conversion of the latter. A derivative may differ by one or more atoms, or functional groups. A metabolite is a stable intermediate compound, or a compound resulting from the biochemical conversion of an initial molecule by metabolism.

[0050] "Pharmaceutically acceptable salt" means an addition salt of a compound obtainable by reaction of the said compound with an inorganic acid or an organic acid by methods known per se. Among the acids conventionally used for this purpose, mention can be made of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, 4-toluenesulfonic acid, methanesulfonic acid, cyclohexylsulfamic acid, oxalic acid, succinic acid, formic acid, fumaric acid, maleic acid, citric acid, aspartic acid, cinnamic acid, lactic acid, glutamic acid and N-acetylaspartic acid, N-acetylglutamic acid, ascorbic acid, malic acid, benzoic acid, nicotinic acid and acetic acid. According to a preferred embodiment, the compound is not in the form of a salt.

[0051] The said compound, in particular ebselen, may be modified in order to increase its stability, its bioavailability and / or its ability to reach the targeted tissue, in particular the mitochondria.

[0052] In a manner known to those skilled in the art, the compound, particularly ebselen, may be present in the composition in its naked form (free), or may be contained in a delivery system such as liposomes that increases stability, targeting and / or bioavailability, or may be incorporated in combination with a hydrogel, cyclodextrin, biodegradable nanocapsule, bioadhesive microsphere, vector or cationic peptide.

[0053] The present invention also relates to a pharmaceutical composition containing at least one compound as an active ingredient, such as those defined above, and to the use of the compound or the composition as a drug or pharmaceutical.

[0054] Accordingly, the present invention targets a pharmaceutical composition comprising a compound according to the invention for targeted use. Advantageously, the composition comprises a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. In certain embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or State government or listed in the United States Pharmacopeia or the European Pharmacopeia generally recognized for use in animals and humans. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle administered together with the therapeutic product. The pharmaceutical carrier can be a sterile liquid such as water and oil, including those of petroleum origin, animal origin, plant origin or synthetic origin, such as peanut oil, soybean oil, sesame oil or others. Aqueous saline solutions and aqueous solutions of dextrose and glycerol may also be used as liquid carriers, particularly for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol and others.

[0055] The composition may also contain, if necessary, trace amounts of wetting agents or emulsifiers or pH buffering agents. The composition may take the form of solutions, suspensions, emulsions, sustained release formulations and others. Examples of suitable pharmaceutical carriers are described in "Remington’s Pharmaceutical Sciences" by E.W. Martin. The composition contains a therapeutically effective amount of a therapeutic agent, preferably in a purified form, and an appropriate amount of a carrier to provide a form suitable for proper administration to a subject.

[0056] In a preferred embodiment, the composition is formulated according to routine procedures, such as a suitable pharmaceutical composition for oral administration to humans, for example. Typically, compositions for oral administration are in the form of tablets, which may in some cases be split tablets or effervescent tablets, and also contain solid dosage forms and excipients applicable for administration to humans. As an example, ebselen can be in the form of a powder packaged in tablets that can contain 200 mg of the active ingredient. The tablets may be crushed and mixed with a liquid.

[0057] Alternatively, the composition may be in liquid form, and advantageously may be a liquid composition. Any other suitable solvent may be used.

[0058] The amount of the therapeutic agent of the present invention that is effective for the treatment of a disease, i.e., a compound such as those described above, may be determined by standard clinical techniques. Furthermore, in vivo and / or in vitro tests such as those described in the following examples may be used in some cases to assist in predicting a suitable dosage range. The exact dosage to be used in the formulation also depends on the route of administration, body weight and severity of the disease and must be determined by the judgment of the practitioner and the condition of each patient.

[0059] According to a particular embodiment, the composition of the present invention is in solid form, and advantageously is a tablet that can contain 200 mg of the active compound, in particular ebselen.

[0060] According to one embodiment, the composition of the present invention is in liquid form and advantageously contains an effective compound, in particular ebselen, at 30 μM, 20 μM or even 15 μM. According to one embodiment, the composition of the present invention is in liquid form and advantageously contains 1 nM or more, even 10 nM or more, 30 nM or more, even 100 nM or more, for example an effective compound, in particular ebselen, at an optimal concentration of 1 μM.

[0061] The appropriate route of administration must be the delivery of a therapeutically effective amount of the therapeutic product to the target tissue, depending on the disease.

[0062] Ebselen and its derivatives may be administered in a pharmaceutically acceptable form by one of the routes of administration known for this type of active ingredient.

[0063] The available routes of administration are topical (local), enteral (systemic action, but delivered via the gastrointestinal (GI) tract), or parenteral (systemic action, but delivered via a route other than the GI tract). In the specific case of mitochondrial diseases, the preferred route of administration of the compositions disclosed herein is generally the enteral route, which includes oral administration, sublingual administration, buccal administration, and preferably oral administration.

[0064] In other embodiments, administration can be by parenteral administration, in particular by the intramuscular route (i.e., inside the muscle) or the systemic route (i.e., the circulatory system). In this context, the term "injection" (or "perfusion" or "drip") encompasses intravascular administration, in particular intravenous (IV) administration and intramuscular (IM) administration. Injections are generally performed using a syringe or a catheter.

[0065] According to one embodiment, the composition is administered via the oral, intramuscular, intraperitoneal, subcutaneous, topical, local or intravascular route, advantageously via the oral route. According to a preferred embodiment, the composition is intended for oral administration.

[0066] The composition according to the present invention is preferably in a solid galenical form suitable for oral administration and advantageously in the form of one or more gel caps or tablets.

[0067] Alternatively, the container can be in the form of a liquid preparation such as an elixir and a suspension containing various masking substances for coloring, flavoring and stabilizing.

[0068] According to a preferred embodiment, the composition is intended for oral administration. Advantageously, the composition is administered orally, i.e., via the mouth.

[0069] Preferably, the composition according to the invention is administered orally, particularly in the form of gel caps, capsules or tablets.

[0070] To produce the oral galenos form according to the invention, particularly gel caps, the active substance may be mixed with various conventional substances such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate in order to facilitate the encapsulation process. Magnesium stearate as an additive provides a useful lubricating function if necessary.

[0071] Under certain circumstances, it may be advantageous to provide a controlled release form, particularly a long-term release by a known galenos form.

[0072] Furthermore, the composition according to the invention may be intended for the preparation of a pharmaceutical composition that can be administered by injection.

[0073] The pharmaceutical composition according to the invention may be dissolved in a sterile injectable liquid such as pharmaceutically acceptable sterile water, a sterile organic solvent or a mixture of the two liquids, or introduced into its suspension for intravenous administration.

[0074] Other routes of administration may include, but are not limited to, subcutaneous implants and oral, sublingual, transdermal, topical, intranasal or rectal administration. Biodegradable and non-biodegradable delivery systems may also be used.

[0075] As already mentioned, the composition according to the invention is preferably in a solid galenical form suitable for oral administration, advantageously in the form of one or more gelcaps or tablets.

[0076] The gelcaps or tablets may be taken with a small amount of water before or during the main meal. According to a preferred embodiment, the composition of the invention is administered, for example, once a day, further two or more times a day, daily. The treatment may be continued for a plurality of weeks, a plurality of months, a plurality of years or even throughout life.

[0077] Generally, the dosage of the therapeutic agent, i.e. one of ebselen or its derivatives, varies according to factors such as age, weight, height, gender, general health and the medical antecedents of the subject. Typically, it is desirable to provide the patient with an individual dose of the therapeutic agent that is non-toxic and effective.

[0078] According to a particular embodiment of the invention, the dosage of the composition, advantageously the daily dosage for human oral intake, is 10 mg, or 9, 8, 7, 6, 5, 4, 3 mg / kg or less, further 2.5, 2, 1.5 or 1 mg / kg or less, further 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.1 mg / kg or less.

[0079] As already shown, the patient is advantageously a human, in particular a neonate, infant, child, adolescent or adult, regardless of their gender. However, the treatment tool according to the invention may be suitable and useful for the treatment of other animals, in particular pigs, mice, dogs or rhesus monkeys.

[0080] Generally, the invention relates to the treatment of generally mitochondrial diseases, i.e. diseases related to mitochondrial dysfunction or diseases caused by mitochondrial dysfunction. In the context of the present application, the term "diseases related to mitochondrial dysfunction" is used to encompass all such situations.

[0081] Regarding the following examples demonstrating a positive effect of ebselen or one of its derivatives in the mitochondrial respiratory chain, the diseases of particular interest are mitochondrial respiratory chain diseases.

[0082] Multiple mitochondrial diseases have been documented in the prior art: NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) induces various combinations of late onset, retinitis pigmentosa, dementia, epileptic seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy. The NARP syndrome is caused by various mutations in the mitochondrial gene ATP6, which encodes subunit α of ATPase (complex V of the OXPHOS system). Mutations often show heteroplasmy (coexistence of mutant and wild type (WT) mitochondrial DNA (mtDNA) in the same cell). Depending on the type of mutation and the percentage of mutant mtDNA (degree of heteroplasmy), the clinical outcomes vary in severity. The ATP6:m.8993T>C / G mutation is the most frequent in NARP patients causing severe forms of the NARP syndrome. FMC1 is a nuclear gene encoding a protein that is required at high temperature (35 - 37°C) for the construction of sector F1 of ATP synthase, thereby mimicking the heteroplasmy observed in patients with NARP. Indeed, when cultured at the restrictive temperature (35 - 37°C), the mitochondria of the mutant fmc1Δ contain even fewer assembled ATP synthase complexes than the wild type (WT) strain, but the assembled ones are fully functional. This heterogeneity is also seen in patients with reduced levels of ATP synthase due to heteroplasmic mutations in the ATP6 gene. As a result, the mutant fmc1Δ constitutes a suitable model for this disease, particularly a model equivalent to the mutant m.8993T<G (MR14, NARP) (Schon EA et al. (2001) Cell Dev Biol. 12(6):441 - 8).

[0083] The TAZ gene encodes tafazzin, a mitochondrial transferase that catalyzes the remodeling of immature cardiolipin into its mature composition containing a preponderance of tetralinoleoyl fragments. <3980>TAZ<!--3980-->Mutations in TAZ cause Barth syndrome, an X-linked disorder classically characterized by dilated cardiomyopathy (CMD) with endocardial fibroelastosis (EFE), proximal dominant skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly 3-methylglutaconic acid (Barth, P.G. et al. (1996) J Inherit Metab Dis, 19, 157-160).

[0084] The genes COX2 and SURF1 encode a subunit and an assembly factor of mitochondrial complex IV, respectively. Mutations are associated with Leigh syndrome, a severe progressive neurodegenerative disorder that presents in the first month and year of life and is a cause of early death. Affected individuals generally have global developmental delay, developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities such as nystagmus or optic atrophy (Barrientos, A. et al. (2002) EMBO J, 21, 43-52).

[0085] MPV17 encodes a protein of the mitochondrial inner membrane, but its function is unknown. Mutations in MPV17 result in:

[0086] - Mitochondrial DNA depletion syndrome, an autosomal recessive disorder characterized by the onset of progressive liver failure in infancy, often leading to death within the first year of life. Surviving infants develop progressive neurological impairment, particularly ataxia, hypotonia, dystonia, and psychomotor developmental regression (Spinazzola, A. et al. (2006) Nat Genet, 38, 570-575).

[0087] - Navajo - type neuropathy: Symptoms include corneal ulceration caused by severe anesthesia, painless fractures, limb amputations, muscle weakness, absence or marked decrease of deep tendon reflexes without intellectual impairment (Karadimas, C.L. et al. (2006) Am J Hum Genet, 79, 544 - 548).

[0088] Particularly interesting are the treatments of diseases selected from the group consisting of MELAS syndrome, maternally inherited myopathy or cardiomyopathy, NARP or MILS syndrome, Leigh syndrome, Leber hereditary optic neuropathy (LHON), Barth syndrome, mitochondrial DNA depletion syndromes, particularly 4A (Alpers type) and 4B (MNGIE type), mitochondrial recessive ataxia syndrome, sensory ataxic neuropathy, dysarthria and ophthalmoplegia, spinocerebellar ataxia with epilepsy, progressive external ophthalmoplegia, mitochondrial DNA6 depletion syndrome, Navajo - type neuropathy, Bjerre syndrome, mitochondrial DNA14 depletion syndrome, infantile encephalomyopathy due to cytochrome c oxidase deficiency (COA6 mutation), mitochondrial complex I nuclear deficiency of complex III, GRACILE syndrome, and Björnstad syndrome.

[0089] The treatment of diseases associated with mitochondrial complex I deficiency is particularly interesting. Certain diseases are specifically related to complex I dysfunction, while other diseases are related to multiple deficiencies affecting, for example, multiple mitochondrial complexes.

[0090] In a known manner, the respiratory chain in mitochondria is involved in oxidative phosphorylation. This is an important cellular process that uses oxygen and monosaccharides to create adenosine triphosphate (ATP), the main energy source for cells. Five protein complexes make up the OXPHOS system, each composed of multiple proteins, and these are involved in this process. These complexes are called Complex I, Complex II, Complex III, Complex IV, and Complex V, respectively. Complex I (CI or NADH dehydrogenase or NADH coenzyme Q reductase), the first enzyme of the respiratory chain, is a very large protein complex (about 1000 kDa) composed of at least 44 subunits, including seven (ND1 - ND6 and ND4L) encoded by mitochondrial DNA.

[0091] According to certain embodiments, the compounds according to the invention, in particular ebselen, can be used to treat diseases resulting from identified genetic abnormalities that are identified in at least one subunit of an OXPHOS complex (in particular Complex I) associated with so-called "primary" mitochondrial diseases, i.e., one or more mitochondrial or nuclear DNA mutations. These pathologies are related to neurological disorders, myocardial or ophthalmological symptoms related to the tissues or organs most affected by these mitochondrial diseases, even if in some cases other organs or tissues are affected.

[0092] According to certain embodiments, the compounds according to the invention, in particular ebselen, can be used to treat so-called "secondary" mitochondrial diseases. In this case, the genetic abnormalities are not directly involved in the OXPHOS complex, but the pathology affects mitochondrial function and can in particular cause a decrease in the enzymatic activity of this process. Such diseases can also be caused by genetic causes such as exposure to environmental factors or aging. This is particularly the case for Parkinson's disease or other age-related neurodegenerative disorders.

[0093] According to a preferred embodiment, a genetic disease is caused by a deficiency or mitochondrial dysfunction.

[0094] A genetic disease, by definition, is a disease that results from one or more genetic defects (abnormalities) (or mutations) in one or more genes. Genetic defects can affect mitochondrial DNA and / or nuclear genes. The genetic defects causing mitochondrial diseases can be isolated mutations that cause codon changes. However, the disease can be related to deletions or insertions of one or more bases or codons.

[0095] According to a particular embodiment, the disease results from one or more genetic defects (or mutations) in one or more genes involved in the functionality of the OXPHOS complex, particularly complex I.

[0096] A non-limiting list of such genes is: - Complex I building genes, particularly MTND1 (or ND1), MTND2 (or ND2), MTND3 (or ND3), MTND4 (or ND4), MTND5 (or ND5), MTND6 (or ND6), MTND4L (or ND4L), NDUFA1, NDUFA2, NDUFA3, NDUFA4, NDUFA5, NDUFA6, NDUFA7, NDUFA8, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAB1, NDUFB1, NDUFB2, NDUFB3, NDUFB4, NDUFB5, NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFB10, NDUFB11, NDUFC1, NDUFC2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFV3, - Complex I assembly genes, particularly including NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF7, NDUFAF8, NUBPL, ACAD9, TMEM70, TMEM126B, FOXRED1, ECSIT, AIF, TIMMDC1.

[0097] According to certain embodiments, the diseases treated within the framework of the present invention relate to, or are caused by, at least one genetic defect or mutation in at least one of the following genes: MTTL1, ATP6, FMC1, TAZ, COX2, SURF1, POLG, MPV17, OPA1, COA6, ND6, and BCS1L, preferably at least one of ATP6, TAZ, COX2, and SURF1.

[0098] Multiple mitochondrial diseases associated with genetic origin, particularly deficiencies of mitochondrial complex I, have been documented in the prior art. Leber's hereditary optic neuropathy (LHON) or Leber's optic atrophy generally presents in young adults. The onset is sudden and is accompanied by a rapid loss of vision in the center of the eye corresponding to a decrease in central vision. In most cases, the peripheral visual field is present as a visual halo around the blind spot. This disease is caused by common homoplasmic mutations in the genes encoding subunits of complex I of the respiratory chain. In fact, the mitochondrial DNA mutations m.11778G>A, m.3460G>A, and m.14484T>C represent approximately 95% of LHON mutations.

[0099] Leigh syndrome (LS) is a severe neurodegenerative disease. Affected individuals generally have global developmental delay, developmental regression, hypotonia, ataxia, dystonia, and ophthalmological abnormalities such as nystagmus or optic atrophy. Leigh syndrome can also have multi-organ effects that are harmful to the heart, liver, gastrointestinal tract, and kidneys. Biochemical investigations in patients with Leigh syndrome tend to show increased lactate and abnormal mitochondrial oxidative phosphorylation. Leigh syndrome may be associated with mutations in genes encoding subunits of complex I, such as the mutation NDUFV1 or the mutation MTND5 m.13513G>A.

[0100] MELAS syndrome, which includes mitochondrial myopathy, brain disease, lactic acidosis, and episodic seizures, is a genetically heterogeneous mitochondrial disease with various clinical phenotypes. This disorder is characterized by central nervous system damage, particularly with seizures, hemiplegia, hemianopia, cortical blindness, and sudden vomiting. This syndrome was first induced by the denaturation of the translation of the mRNA of protein complex I, and thus induced a decrease in the amount of structural proteins of complex I such as mitochondrial subunit ND6, a mutation in mitochondrial DNA m.3243A>G, that is, the gene tRNA Leu(UUR) (MTTL1). MELAS syndrome may also be associated with other mitochondrial DNA mutations such as m.3260A>G, which also affects tRNA Leu(UUR) . The mutation m.3260A>G may also result in other clinical phenotypes, particularly myopathy or cardiomyopathy of maternal origin.

[0101] Therefore, the treatment of genetic diseases that have been demonstrated to be associated with complex I deficiency, such as MELAS syndrome, Leigh syndrome, and Leber hereditary optic neuropathy (LHON), is of particular interest. Note that the disease may be associated with other symptoms such as heart, myopathy, or neurological clinical phenotypes.

[0102] More generally, the compounds according to the invention, in particular ebselen, may be used to treat mitochondrial dysfunction, particularly mitochondrial dysfunction associated with complex I deficiency. Mitochondrial dysfunction, characterized by a loss of efficiency of the electron transport chain and a decrease in the synthesis of high-energy molecules such as adenosine-5'-triphosphate (ATP), is a feature of aging and generally all chronic diseases.

[0103] Such diseases include - neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and Friedreich's ataxia; - cardiovascular diseases such as atherosclerosis and other cardiovascular diseases; - Diabetes and metabolic syndrome; - Autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus and type 1 diabetes; - Neurokinetic and mental illnesses such as autism spectrum disorder, schizophrenia, bipolar disorder and mood disorders, - Gastrointestinal disorders, - Fatigue diseases such as chronic fatigue syndrome and Gulf War syndrome; - Musculoskeletal diseases such as fibromyalgia and skeletal muscle hypertrophy / atrophy; - Muscular dystrophy, - Cancer; and - Chronic infections are included.

[0104] The treatment recommended by the present invention is based on one of ebselen or its derivatives, which may also be related to other treatments intended to treat the same pathological condition, or the same state, or another disease.

[0105] According to certain embodiments, said other treatment is based on the administration of another compound of interest.

[0106] Thus, according to this aspect, the compositions of the present invention are related to at least one other compound for the treatment of the same disease. The compositions and said compounds according to the present invention can be administered simultaneously or separately over time in order to take into account their characteristics, in particular their bioavailability.

[0107] According to one particular mode of application, the present invention relates to compositions, preferably pharmaceutical compositions or drugs containing compounds such as those described above, for treating the same or different diseases, preferably the same disease, and potentially other active molecules (other gene therapy molecules, chemical moieties, peptides or proteins).

[0108] Preferably, the pharmaceutical compositions according to the present invention and at least one compound for treating the same or different diseases are administered simultaneously, separately or spread over time for treating the same or different diseases.

[0109] More generally, with regard to mitochondrial diseases, another compound capable of improving mitochondrial function may be administered simultaneously or at different times. In the case of simultaneous administration, the two compounds may be combined in the same composition.

[0110] Examples of such additional compounds are natural supplements such as L-carnitine, alpha-lipoic acid (α-lipoic acid [1,2-dithiolane-3-pentanoic acid]), coenzyme Q10 (CoQ10 or ubiquinone), riboflavin (vitamin B2) reduced in nicotinamide adenine dinucleotide (NADH), L-arginine, etc., which may in some cases be combined.

[0111] For example, examples of compounds used in the case of MELAS syndrome are nitric oxide (NO) precursors such as L-arginine and citrulline.

[0112] According to certain embodiments, and from the perspective of the examples demonstrating potential synergistic effects, the compound according to the invention, in particular ebselen, is combined with one of the compounds described in WO 2020 / 254632 pamphlet and WO 2022 / 018297 pamphlet, preferably with one of the compounds selected from the group consisting of disulfiram, sodium diethyldithiocarbamate, alverine and alverine citrate.

[0113] Subjects who can benefit from the composition according to the invention include all patients diagnosed with a disease associated with mitochondrial dysfunction, in particular mitochondrial dysfunction associated with complex I deficiency, carriers of such a disease or carriers at risk of developing such a disease.

[0114] The subjects to be treated with the composition according to the invention may be selected based on different criteria. With regard to mitochondrial dysfunction, in particular complex I deficiency, for example: - Multiple tests can be performed regarding biochemical levels and O2 consumption, and / or mitochondrial complex I activity can be measured from a biopsy from a subject, particularly muscle or skin. The activity of other complexes of the respiratory chain can also be - At the genetic level, which is identified by sequencing mitochondrial DNA or nuclear DNA extracted from cells or biopsy samples such as, for example, from skin, particularly by one or more molecular abnormalities such as mutations or deletions / insertions in the genes listed below, it may be evaluated whether mitochondrial dysfunction is due only to complex I deficiency. Alternatively, the expression or activity of the corresponding protein may be evaluated by any method known to those skilled in the art (e.g., by Western blot).

[0115] An object of the present invention is to provide a safe (non-toxic) treatment. Another object is to provide an effective treatment that can retard, delay or prevent the onset of the disease and, in some cases, improve the phenotype of the patient that can be monitored at the clinical level as shown below.

[0116] For a subject, the composition according to the present invention - To improve mitochondrial function, particularly mitochondrial respiration, - To improve growth, - To improve muscle function, - To improve vision and / or hearing, - To improve cardiac function, liver function or kidney function, - To improve brain function, - To improve digestive function, and / or - Can be used to extend the survival period, more generally to improve the quality of life and life expectancy.

[0117] According to one aspect, the present invention relates to a method for improving mitochondrial function, particularly complex I activity, advantageously without undesirable effects, including administration to a subject in need of a therapeutic amount of a composition such as those described above.

[0118] Advantageously, the improvement is observed up to a maximum of 1 month, or 3 months, or 6 months, or 9 months after the start of treatment, more advantageously up to a maximum of 1 year, 2 years, 5 years, 10 years or even over the entire lifetime of the subject after the start of treatment.

[0119] In one embodiment, the improvement appears as a reduction in the severity and / or frequency of symptoms, and / or as a retarded appearance.

[0120] The improvement can be evaluated based on methods known in the art. For example, in the case of MELAS, - evaluation of lactate, particularly the amount of lactate in the ventricles, measured by magnetic resonance spectroscopy (MRS), - evaluation of quality of life and / or life expectancy using a clinical scale, such as the Newcastle Mitochondrial Disease Scale for Adults (NMDAS) score or the Short Form Health Survey (SF-36) score, - evaluation of brain modifications using, for example, magnetic resonance imaging (MRI), - evaluation of changes in muscle activity by a physical test such as a 6-minute walk test, - evaluation of changes in venous lactate and the concentration of GDF15, - evaluation of mtDNA heteroplasmy changes in urine and blood.

[0121] The parameters suitable for a given case can be adapted according to the disease.

[0122] Thus, the claimed treatment makes it possible to improve the clinical condition and the different parameters disclosed above with respect to untreated subjects.

[0123] The practice of the present invention uses conventional techniques of molecular biology (recombinant technology), microbiology, cell biology, biochemistry and immunology, unless otherwise specified. These are known to those skilled in the art. These techniques are described in detail, inter alia, in the literature such as "Molecular Cloning: A Laboratory Manual", fourth edition (Sambrook, 2012), "Oligonucleotide Synthesis" (Gait, 1984), "Culture of Animal Cells" (Freshney, 2010), "Methods in Enzymology", "Handbook of Experimental Immunology" (Weir, 1997), "Gene Transfer Vectors for Mammalian Cells" (Miller and Calos, 1987), "Short Protocols in Molecular Biology" (Ausubel, 2002), "Polymerase Chain Reaction: Principles, Applications and Troubleshooting" (Babar, 2011), "Current Protocols in Immunology" (Coligan, 2002). Techniques particularly useful for specific embodiments are described in the following sections.

[0124] The disclosures of the patents, patent applications and patent application publications cited in this application are incorporated by reference in their entirety.

[0125] In the absence of further explanation, those skilled in the art can manufacture and use the compounds of the present invention and practice the claimed methods by using the description and the following exemplary embodiments.

Examples

[0126] The present invention and the advantages arising therefrom will become more apparent from the following examples of embodiments supported by the related figures. However, these have no limiting consequences.

Brief Description of the Drawings

[0127]

Figure 1

[0128]

Figure 2

[0129]

Figure 3

[0130]

Figure 4

[0131]

Figure 5

[0132]

Figure 6

[0133]

Figure 7

[0134]

Figure 8

[0135]

Figure 9

[0136] (Examples 1 to 3)

[0137] Saccharomyces cerevisiae model Each of the strains of the yeast Saccharomyces cerevisiae used in these examples contains different specific mutations that model human mutations causing mitochondrial diseases. To varying degrees, all of these mutant yeast strains have a growth defect when cultured on respiratory media such as ethanol or glycerol at 28 °C or 36 °C (depending on the strain).

[0138] Mutant yeast strains: - fmc1 for the first screening: MC6 MATa ade2-1 his3-11,15 trp1-1 leu2-3,112 ura3-1 fmc1::HIS3 [Δi ER OR](Schwimmer,C.et al.(2005)J Biol Chem,280,30751-30759) - MR14 for the second screening: MATa ade2-1 his3-11,15 trp1-1 leu2-3,112 ura3-1 CAN1 arg8::HIS3 ρ+ atp6-L173R or RKY20 MATa ade2-1 his3-11,15 trp1-1 leu2-3,112 ura3-1 CAN1 arg8::HIS3 ρ+ atp6-L173P (Rak,M.et al.(2007)J Biol Chem,282,34039-34047) -taz1Δ: This strain was generated by replacing the open reading frame of TAZ1 with that of TRP1 in the strain W303-1A (MATa ade2-1 ura3-1 his311,15 trp1-1 leu2-3,112 can1-100) (by Taffin de Tilques, M. et al. (2017) Dis Model Mech, 10, 439-450). -shy1-G137R: This variant was generated in the strain CW252, which contains a mitochondrial gene lacking the nuclear bases and introns of W303. This gene is a homolog of the human gene SURF1 -sym1Δ: This yeast strain was generated by replacing the open reading frame of SYM1 with that of kanMX6 in the strain W303-1A (MATa ade2-1 ura3-1 his311,15 trp1-1 leu2-3,112 can1-100). This gene is a homolog of the human gene MPV17 -cox2: MATa lys2 leu-2-3,112 ura3-52 his3ΔHindIII arg8::hisG cox2-22 (Bonnefoy, N. et al. (2001) Mol Cell Biol, 21, 2359-2372).

[0139] -A29G: Yeast strains used in these experiments include tRNA-LeuA29G with the genetic bases MATα, his3-11, ade2-1, leu2-3,112, ura3-1, trp1-D2, can1-100, syn.

[0140] Related mitochondrial diseases: NARP syndrome NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) induces various combinations of late onset, retinitis pigmentosa, dementia, epileptic seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy. NARP is caused by various mutations in the mitochondrial gene ATP6, which encodes the subunit α of ATPase (complex V of the OXPHOS system). Mutations often show heteroplasmy (coexistence of mutant and wild type (WT) mitochondrial DNA (mtDNA) in the same cell). Depending on the type of mutation and the percentage of mutant mtDNA (degree of heteroplasmy), the clinical outcomes vary in severity. The ATP6:m.8993T>C / G mutation is the most frequent in NARP patients who develop a severe form of the NARP syndrome. FMC1 is a nuclear gene that encodes a protein that is required at high temperature (35 - 37°C) for the construction of the sector F1 of ATP synthase, thereby mimicking the heteroplasmy observed in patients with NARP. Indeed, when cultured at the restrictive temperature (35 - 37°C), the mitochondria of the mutant fmc1Δ contain fewer assembled ATP synthase complexes than the wild type (WT) strain, but the assembled ones are fully functional. This heterogeneity is also seen in patients with reduced levels of ATP synthase due to heteroplasmic mutations in the ATP6 gene. As a result, the mutant fmc1Δ constitutes an appropriate model for the disorder (Lefebvre-Legendre, L. et al. (2001) J Biol Chem, 276, 6789 - 6796). Various NARP yeast strains with homoplasmic mutations equivalent to the mutations T8993G and T8993C (Rak, M. et al., J Biol Chem. 2007 282(47):34039 - 47) were also tested.

[0141] TAZ The TAZ gene encodes tafazzin, a mitochondrial transferase that catalyzes the remodeling of immature cardiolipin to its mature composition containing a preponderance of tetralinoleoyl fragments. <6920>TAZ<!--6920-->Mutations cause Barth syndrome, which is an X chromosome-related disease and is characterized by dilated cardiomyopathy (CMD) with endocardial fibroelastosis (EFE), proximal dominant skeletal myopathy, growth retardation, neutropenia, and organic aciduria, especially 3-methylglutaconic acid (Barth, P.G. et al. (1996) J Inherit Metab Dis, 19, 157-160).

[0142] COX2 and SURF1 The genes COX2 and SURF1 (the SHY1 gene in yeast) encode a subunit and an assembly factor of mitochondrial complex IV, respectively. Mutations are associated with Leigh syndrome, a severe progressive neurodegenerative disease that appears at 1 month and 1 year of age and can cause early death. Affected individuals generally have global developmental delay, developmental regression, hypotonia, ataxia, dystonia, and ophthalmological abnormalities such as nystagmus or optic nerve atrophy (Barrientos, A. et al. (2002) EMBO J, 21, 43-52).

[0143] MPV17 MPV17 (the SYM1 gene in yeast) encodes a protein of the mitochondrial inner membrane, but its function is unknown. MPV17 mutations result in the following:

[0144] - Mitochondrial DNA depletion syndrome, an autosomal recessive disease characterized by the appearance of progressive liver failure in infants, often leads to death within the first year of life. Surviving infants develop progressive neurological damage, especially ataxia, hypotonia, dystonia, and psychomotor developmental regression (Spinazzola, A. et al. (2006) Nat Genet, 38, 570-575).

[0145] - Navajo - type neuropathy: Symptoms include severe sensorimotor peripheral neuropathy with liver and brain damage such as leukoencephalopathy and corneal tumors (Karadimas, C.L. et al. (2006) Am J Hum Genet, 79, 544 - 548).

[0146] - MELAS syndrome: The mutation A30(29)G in yeast A29G mimics the human mutation m.3260A>G in the gene tRNALeu(UUR), which is the cause of MELAS syndrome.

Example 1

[0147] Effects of Ebselen (EBS) and its derivatives on mutant yeast strains cultured in a non - fermentative (respiratory) environment Materials and methods

[0148] As previously described (International Publication No. WO 2020 / 254632 pamphlet), different mutant yeast strains were spread on solid respiratory agar - agar - based media (containing glycerol or ethanol as the sole carbon source), and exposed to filters deposited with the compound to be tested, particularly Ebselen (EBS). The plates were then incubated at the indicated temperature (which can be 28 °C or 36 °C depending on the strain used).

[0149] More precisely, exponentially growing variant cells at 0.125 OD were evenly spread with sterile glass beads in square Petri dishes (12 cm × 12 cm) containing solid respiratory medium (YPA ethanol, 1% yeast extract, 0.5% Bacto peptone, 40 mg / L adenine, 2% ethanol for sym1 and taz1, or YPA glycerol 2% for cox2, fmc1, atp6, shy1 and A29G). Then, a small sterile filter was placed on the agar-agar surface, and the test compound at the indicated amounts (30 and 90 nmole) for the growth concentration was added to the filter. In each dish, DMSO (buffer) was used as a negative control (upper left filter). The dishes were then incubated at 28 °C (for shy1) or 36 °C (for cox2, sym1, fmc1, atp6 taz1 and A29G) for 4 - 5 days and then photographed. The improvement in growth was evaluated after several days of incubation by the appearance of a halo of improved growth around the filter on which the active ingredient was deposited. Results

[0150] As can be seen in Figure 1A, EBS is effective in all the mutant yeast strains tested in a dose-dependent manner.

[0151] For the mutant taz1, Figure 1C shows that ebselen oxide (100 nmole) has an activity corresponding to that of ebselen (100 nmole) (Figure 1B), but no halo was observed in the presence of DMSO (Figure 1D).

[0152] More generally, different analogs of EBS and etaselen were evaluated in different mutants (taz1, fmc1, cox2 and A29G). As shown in Figure 1E, all the analogs tested are effective in the strains tested.

Example 2

[0153] Effect of ebselen (EBS) on the mutant yeast strain taz1 Materials and methods

[0154] Respiratory growth in liquid culture: To determine the optimal concentration of EBS that causes suppression of defective respiratory growth in the mutant yeast strain, exponentially growing cells were inoculated into fresh ethanol YPA non-fermentable medium supplemented or not supplemented with increasing concentrations of EBS. Cell growth in the liquid respiratory medium was monitored using a Bioscreen system over an 80-hour period while sampling the (OD600nm) cell density every 20 minutes.

[0155] B / Cell respiration: Respiratory intensity corresponds to the amount of oxygen consumed with respect to time and cell number. This reflects the mitochondrial oxidative metabolism of the cells. Oxygen consumption was measured using an OROBOROS oxygraph system. Cells were cultured in ethanol YPA medium supplemented with DMSO or EBS (1 μM) at 28 °C for 7 - 8 generations over 24 - 48 hours. 10 7 Individual cells were introduced into the oxygraph. Oxygen consumption was recorded with or without CCCP (maximum oxygen consumption rate). The oxygen consumption rate was calculated based on the linear portion of the oxygen consumption.

[0156] Accumulation of Cox2 protein: Total protein extracts from the mutant yeast strain were analyzed by SDS-PAGE (50 μg per well) using an antibody against the indicated protein. The gels shown are representative of at least three experiments. Protein levels were quantified using ImageJ software. The level of Cox2 was normalized with respect to Ade13p and represented relative to the wild-type (WT) strain. Results

[0157] As shown in Figure 2A, EBS was toxic at 27 μM, effective at 1 nM - 3 μM, and the optimal concentration was 1 μM in the mutant strain taz1.

[0158] Furthermore, as shown in Figure 2B, 1 μM of EBS increased the accumulation of the protein Cox2, which is a subunit of complex IV of the mitochondrial respiratory chain in the mutant strain taz1.

Example 3

[0159] Effect of ebselen (EBS) on mutant yeast strain sym1 The experiment described in Example 2 was performed with the mutant yeast strain sym1.

[0160] The results are shown in Figure 3.

[0161] Data are mean ± SEM of at least three independent experiments. The significance of the variation between samples and controls was estimated using a multivariate Anova: Tukey test.

[0162] For the mutant strain taz1, at the optimal concentration of EBS (1 μM), the levels of cell respiration and Cox2 increased compared to untreated cells.

Example 4

[0163] Podospora anserina model The yeast Saccharomyces cerevisiae used in Examples 1 - 3 does not have complex I of the mitochondrial respiratory chain. Therefore, EBS was tested in Podospora anserina, a strict filamentous fungus.

[0164] The strain used in the following example contains a specific mutation that models a human mutation in subunit NDUFV1 of complex I, which causes mitochondrial disease. This strain has a growth defect at non - permissive temperatures above 31.5°C.

[0165] P. anserina mutant strain: nuo - 51 A357V: The mutation A357V was incorporated into the nuo-51 gene of the wild-type strain S along with the nourseothricin (NatR) resistance cassette. To mimic the human disease NDUFV1 A341V, the genes NDI-1 and AOX were inactivated (El-Khoury et al., (2008) Curr Genet. 53:249-58). Genotype of the strain: S, mat, nuo-51 A357V , Δndi-1, Δaox, Nat R , Hygro R Materials and Methods

[0166] Thermosensitive mutant Pa nuo-51 A357V was evenly spread on the sterile glass beads of a square Petri dish containing solid minimal medium (M2). Subsequently, a small sterile filter was placed on the agar-agar surface, and 20 nmole of EBS was added. DMSO (the vehicle of the compound) was used as a negative control. Then the plates were incubated at the non-permissive temperature of 33 °C for 4 - 5 days.

[0167] Subsequently, the mutant Pa nuo-51 A357V was cultured at 32 °C, and its growth was decreased with respect to the wild-type (WT) strain. The effect of EBS on the growth rate of the mutant was determined in supplemented minimal medium or at concentrations of EBS that did not increase, and the growth per day was estimated in centimeters (cm / day). Results

[0168] Figure 4A shows the positive effect of EBS on the growth of the mutant. More precisely, at 0.003 - 0.03 μM, EBS demonstrated a significant improvement in the growth of the mutant Pa nuo-51 A357V (Figure 4B).

Example 5

[0169] Human cell model Materials and Methods

[0170] Statistical analysis was performed using a statistical test ANOVA with two mixed factors, applying Bonferroni's multiple test correction, or using Glaspad software prism 9.5.1.

[0171] The number of stars indicates values less than 0.05 (*), less than 0.001 (**), less than 0.0001 (***), less than 0.0001 (****).

[0172] Fibroblasts and myoblasts from TAZ patients: In contrast to fibroblasts from eight different patients (suffering from Barth syndrome) who are carriers of mutations in the TAZ gene, the effect of EBS on the respiratory growth of fibroblasts from TAZ patients was tested. The data show the percentage of growth compared to T0.

[0173] The growth rate was measured using the sulforhodamine B (SRB) staining protocol 24, 48, 72, or 96 hours after plating cells with or without 12.15 nM EBS in a 384-well microtiter plate (1200 cells / well at T0) with a medium containing low glucose (1 g / L; to make the cells use the OXPHOS system rather than the glycolysis system) at low concentrations.

[0174] The growth rate was then measured under the same experimental conditions but using various concentrations of EBS. Cells were treated with increasing doses (150 pM - 234.9 μM) of EBS and analyzed after 96 hours. The data are the mean of 8 patients or 3 controls repeated 3 times in 4 independent experiments.

[0175] The growth rate was then measured under the same experimental conditions but using various concentrations of etacelestine. Cells were treated with increasing doses (150 pM - 26.1 μM) of etacelestine and analyzed after 96 hours. The bars represent the mean of 4 replicates from 2 patients in 3 independent experiments.

[0176] The Promega CellTiter-Glo kit was used to evaluate the level of mitochondrial ATP in fibroblasts from TAZ patients. Cells (5000 cells / well) in 96-well plates were treated with 12.15 nM EBS for 96 hours or left untreated, and then incubated in the presence of antimycin A (100 μM), rotenone (0.5 μM) or oligomycin A (3 μM).

[0177] EBS was also tested for its ability to restore cell proliferation in myoblast cell lines derived from patients who are carriers of mutations in the TAZ gene. The growth rate was measured using the sulforhodamine B (SRB) staining protocol in 384-well microtiter plates (1200 cells / well at T0) with medium containing low glucose at 48 hours, 72 hours, 96 hours or 120 hours after cell seeding. The graph shows the growth rate at 120 hours corresponding to the average of three independent experiments.

[0178] KO ("knockout") cell line FMC1: A cell line HeLa KO FMC1 that mimics human diseases (NARP, MILS syndrome) associated with ATP synthase deficiency was generated by the CRISPR-Cas9 method. The cell line HeLa KO FMC1 was cultured in DMEM medium containing 4.5 g / L glucose, 110 mg / L pyruvate and 50 mg / L uridine.

[0179] The growth rate of this HeLa cell line with depleted gene FMC1 was measured using the sulforhodamine B (SRB) staining protocol in 384-well microplates (4500 cells / cm 2 ) at 96 hours after cell seeding and treatment, with medium containing either low glucose (1 g / L) or low galactose. The bars represent the average of 8 replicates from 3 independent experiments. The data show the percentage of growth compared to T0.

[0180] KO (knockout) cell line CI (complex I): EBS also tested the ability of the fibroblast cell line of patients with mutations in the nuclear gene NDUFV1 of mitochondrial complex I to restore mitochondrial respiration. The human cell line NDUFV1, which mimics human diseases (Leigh syndrome) associated with mitochondrial deficiencies in complex I, is a carrier of gene mutations that affect the gene NDUFV1. These cell lines were cultured in DMEM medium containing 1.0 g / L glucose, 1 mM sodium pyruvate, and 50 μg / mL uridine (Sigma Aldrich, Lyon, France).

[0181] Respiration was measured using a Seahorse XF96 extracellular flux analyzer in 96-well plates according to the manufacturer's protocol (Agilent Technologies). Deficient cells were exposed to different concentrations over 48 hours. The dose-response curve is related to the concentration range of 25 nM to 10 μM. (A) shows the oxygen consumption rate, (B) shows the basal respiration, (C) shows the respiration related to ATP synthase, and (D) shows the maximum respiration. The bars represent the mean of 4 independent replicates.

[0182] Primary fibroblasts in the exponential growth phase were detached by adding 2 mL of trypsin (0.05%). Using these fibroblasts, XF96 plates (30×10 3 cells / well) were seeded and cultured for 4 hours. Then the cells were incubated in a CO2-free incubator for 1 hour in DMEM without bicarbonate supplemented with 5.5 mM glucose and 2 mM L-glutamine (Sigma-Aldrich).

[0183] The measured values of oxygen consumption rate (OCR) were recorded under basal conditions to evaluate mitochondrial respiratory activity, and then the cells were continuously treated with 4 μg / mL of oligomycin and 1.5 μM of carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) (Sigma - Aldrich). Basal OCR, respiration related to ATP, maximal respiratory capacity, and respiration due to proton leak were determined. Non - mitochondrial respiration (OCR after treatment with 2 μg / mL of antimycin A) was subtracted from all OCR measurements. Respiration related to ATP (R - O) production was estimated from the difference between the basal respiration rate and the respiration rate suppressed by oligomycin, and respiration due to proton leak was obtained by subtracting non - mitochondrial respiration from the ROC measured after treatment with oligomycin. Maximal respiratory capacity was measured as the respiration rate in the presence of uncoupled FCCP. The results were normalized according to the number of cells. Results

[0184] Figure 5A shows that 12.15 nM of EBS improves the respiratory growth of fibroblasts from patients with TAZ. At this concentration, EBS is effective after 24 hours, and the improvement in cell proliferation is more significant at three sampling times (48 hours, 72 hours, and 96 hours).

[0185] Figure 5B shows that at 96 hours, EBS improves the respiratory growth of fibroblasts from patients with TAZ over a wide range of concentrations, and EBS has a beneficial effect at 1.35 nM - 8.7 μM with toxicity exceeding 234.9 μM with respect to the negative control DMSO.

[0186] Figure 5C shows that at 96 hours, ethacrynol improves the cell proliferation of patients suffering from Barth syndrome over a wide range of concentrations from approximately 1 nM to 3 μM.

[0187] Figure 5D shows that EBS at a concentration of 12.15 nM improves mitochondrial ATP production in fibroblasts from patients with TAZ.

[0188] The effect of EBS on the recovery of the growth of a myoblast cell line from a patient with a mutation in the TAZ gene is shown in Figure 5E: this shows that EBS at 450 pM to 8.7 μM has a beneficial effect compared to DMSO, which is the negative control, and is toxic above 78.3 μM.

[0189] Figure 6 shows that ebselen improved the growth of model cells of ATP synthase deficiency (NARP, MILS syndrome) in a dose-dependent manner over a wide range of concentrations (pM to μM).

[0190] Figure 7 shows that ebselen improves the respiration of model cells of mitochondrial pathologies associated with complex I, which becomes toxic at 25 nM to 100 nM and above 10 μM.

Example 6

[0191] Synergistic effects between different compounds Disulfiram (DSF) and alverine (ALV) have been reported in WO 2020 / 254632 pamphlet and WO 2022 / 018297 pamphlet as being useful for treating pathologies associated with mitochondrial dysfunction, respectively.

[0192] As a result, possible synergistic effects between ebselen (EBS) and the said compound were tested in different models: - in the -taz mutant yeast model, - in the mutant of complex I of Podospora anserina (Pa nuo-51 A357V ) and - in the -taz mutant mammalian model. Materials and methods

[0193] Taz yeast: As shown in Figure 1, the taz1 mutant yeast strain was spread over a respiratory solid medium containing ethanol as a carbon source. The strain was then exposed to filters deposited with disulfiram (DSF 5 nmole), ebselen (EBS 30 nmole), or alverine (ALV 30 nmole), either alone or in any combination of two or three. The plates were then incubated at a temperature of 36 °C and then scanned 5 days after incubation. DMSO (solvent) was used as a negative control (upper left filter).

[0194] Pa nuo-51 A357V : The growth rate at 32 °C estimated in centimeters per day was determined in minimal medium supplemented with EBS (0.003 μM, 0.01 μM or 0.03 μM), ALV (1 μM) or a combination of both concentrations, compared to DMSO (VEH) at the same concentration per plate.

[0195] Taz mammalian cells: The synergistic effects of EBS, ALV and DSF on the respiratory growth of myoblasts from TAZ patients carriers with mutations in the TAZ gene were tested. The growth rate was measured using the sulforhodamine B (SRB) staining protocol 120 hours after seeding cells seeded with single compounds or related compounds at the indicated concentrations, or not, in a medium containing low glucose (to force cells to use the OXPHOS system rather than the glycolytic system) in 384-well microtiter plates (1200 cells / well at T0). Results

[0196] Figure 8A shows that the combination of the three molecules EBS, ALV and DSF increased the growth halo around the filters deposited in combination, suggesting a synergistic effect of the three candidate drugs on the respiratory growth of the tafazzin-deficient yeast model.

[0197] Figure 8B shows that the combination of 1 μM ALV + 0.003 μM EBS, compared to 1 μM ALV alone, in the mutant Pa nuo-51A357V It has been shown that the growth was significantly increased, suggesting a synergistic effect on the growth of the complex I mutant.

Example 7

[0198] Mouse model of Barth syndrome Materials and methods

[0199] Mice lacking the TAZ gene or the wild-type (WT) gene (Barth syndrome KO model), at 51 days of age, were force-fed 10 mg / kg of ebselen twice a day. The body weight was regularly monitored over a one-month period of treatment. Results

[0200] As shown in Figure 9, the KO mice treated with EBS appeared to have a higher body weight than the mice treated with the solvent.

Claims

1. A pharmaceutical composition for use in the treatment of diseases associated with mitochondrial dysfunction, comprising a compound having the formula moiety:

2. wherein said compound has the formula: wherein each of phenyl rings A and B may optionally be substituted with one or more substituents, each substituent being E is O, S, SO, SO ２ , Se or SeO, and - halogen, preferably halogen selected from among F, Cl and Br, - alcohol, - amine, - nitro, - C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted with one or more halogen atoms preferably selected from among F, Cl and Br, C1-C4 alkyl, and - C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted with one or more halogen atoms preferably selected from among F, Cl and Br, C1-C4 alkoxy, independently selected from among a compound of the formula, a composition for use according to Claim 1.

3. A composition for use according to Claim 2, wherein said compound is one of etacelere or its derivatives such as, for example, MAD423.

4. wherein said compound has the formula: wherein each of phenyl rings A and B may optionally be substituted with one or more substituents, each substituent being - halogen, preferably halogen selected from among F, Cl and Br, E is O, S, SO, SO ２ , Se or SeO, provided that - alcohol, - amine, - nitro, - C1-C4 alkyl such as C1-C2 alkyl or C1 alkyl, each of which may optionally be substituted with one or more halogen atoms preferably selected from among F, Cl and Br, C1-C4 alkyl, and - C1-C4 alkoxy such as C1-C2 alkoxy or C1 alkoxy, each of which may optionally be substituted with one or more halogen atoms preferably selected from among F, Cl and Br, C1-C4 alkoxy, independently selected from among a compound of the formula, a composition for use according to Claim 1.

5. wherein said compound is - 2-phenyl-1,2-benzisoselenazol-3(2H)-one or a compound of the formula: ebselen or - 1-oxide-2-phenyl-1,2-benzisoselenazol-3(2H)-one or a compound of the formula: ​ ​ ​ A composition for use according to claim 4, which is ebselen or an ebselen selenoxide.

6. A composition for use according to any one of claims 1 to 5, wherein the disease is a disease associated with a mitochondrial respiratory chain disease, preferably a complex I deficiency disease.

7. A composition for use according to any one of claims 1 to 6, wherein the disease is a genetic disease.

8. A composition for use according to claim 7, wherein the genetic disease comprises at least one mutation in at least one of the following genes: MTND1 (or ND1), MTND2 (or ND2), MTND3 (or ND3), MTND4 (or ND4), MTND5 (or ND5), MTND6 (or ND6), MTND4L (or ND4L), NDUFA1, NDUFA2, NDUFA3, NDUFA4, NDUFA5, NDUFA6, NDUFA7, NDUFA8, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAB1, NDUFB1, NDUFB2, NDUFB3, NDUFB4, NDUFB5, NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFB10, NDUFB11, NDUFC1, NDUFC2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFV3, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF7, NDUFAF8, NUBPL, ACAD9, TMEM70, TMEM126B, FOXRED1, ECSIT, AIF, TIMMDC1.

9. A composition for use according to claim 7, wherein the genetic disease comprises at least one mutation in at least one of the following genes: MTTL1, APT6, FMC1, TAZ, COX2, SURF1, POLG, MPV17, OPA1, COA6, ND6 and BCS1L, preferably ATP6, FMC1, TAZ, COX2, SURF1 or MPV17.

10. The composition for use according to any one of claims 1 to 9, wherein the disease is selected from the group consisting of MELAS syndrome, maternally inherited myopathy or cardiomyopathy, NARP or MILS syndrome, Leigh syndrome, Leber hereditary optic neuropathy (LHON), Barth syndrome, mitochondrial DNA deletion syndrome, especially 4A (Alpers type) and 4B (MNGIE type), mitochondrial recessive ataxia syndrome, sensory ataxic neuropathy, dysarthria and ophthalmoplegia, spinal cerebellar ataxia with epilepsy, progressive external ophthalmoplegia, mitochondrial DNA 6 deletion syndrome, Navajo type neuropathy, Baelz syndrome, mitochondrial DNA 14 deletion syndrome, infantile encephalomyopathy due to cytochrome c oxidase deficiency (COA6 mutation), mitochondrial complex III nuclear deficiency type I, GRACILE syndrome and Björnstad syndrome.

11. The composition for use according to claim 10, wherein the disease is selected from the group consisting of Leigh syndrome, Leber hereditary optic neuropathy (LHON), MELAS syndrome, NARO or MILS syndrome, Barth syndrome, mitochondrial DNA deletion syndrome and Navajo type neuropathy.

12. The disease is - neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Friedrich's ataxia; - cardiovascular diseases such as atherosclerosis and other cardiovascular diseases; - diabetes and metabolic syndrome; - autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus and type 1 diabetes; - neurobehavioral and mental diseases such as autism spectrum disorder, schizophrenia, bipolar disorder and mood disorder, - gastrointestinal disorders, - fatigue diseases such as chronic fatigue syndrome and Gulf War syndrome; - musculoskeletal diseases such as fibromyalgia and skeletal muscle hypertrophy / atrophy; - muscular dystrophy, - cancer; and - chronic infections, The composition for use according to any one of claims 1 to 7, wherein the composition is selected from the group consisting of

13. The composition for use according to any one of claims 1 to 12, wherein the composition contains another compound for treating the same disease, preferably alverine and / or disulfiram.

14. The composition for use according to any one of claims 1 to 13, wherein the composition is administered orally.

15. The composition according to any one of claims 1 to 14 for use, wherein the composition is in solid form such as a tablet and more preferably contains 200 mg of ebselen.

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