Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
View Patent ↗Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), or Kearns-Sayre Syndrome (KSS) are disclosed, as well as compounds useful in the methods of the invention, such as alpha-tocopherol quinone. Methods and compounds useful in treating other disorders are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.
1. A method of treating a mitochondrial disorder, comprising administering to a subject suffering from the mitochondrial disorder a composition comprising a therapeutically effective amount of one or more compounds of the formula:
where R 11 , R 12 , and R 13 are independently selected from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , or R 13 is H, then at least one of the other two substituents is neither H nor methyl; and all stereoisomers, and mixtures of stereoisomers thereof;
wherein said one or more compounds are the sole active pharmaceutical agent or agents present in a therapeutically effective amount in the composition;
and wherein the mitochondrial disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); Parkinson's disease; amyotrophic lateral sclerosis (ALS); and Huntington's Disease.
2. The method of claim 1 , wherein the one or more compounds are selected from compounds of the formula:
and all stereoisomers, and mixtures of stereoisomers thereof.
3. The method of claim 2 , wherein the one or more compounds is the compound:
4. The method of claim 1 , wherein none of R 11 , R 12 , and R 13 is H and at least one of R 11 , R 12 , and R 13 is not methyl, and all stereoisomers, and mixtures of stereoisomers thereof.
5. The method of claim 1 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
6. The method of claim 1 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
7. The method of claim 1 , wherein the mitochondrial disorder is Parkinson's disease.
8. The method of claim 1 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
9. The method of claim 1 , wherein the mitochondrial disorder is Huntington's Disease.
10. The method of claim 2 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
11. The method of claim 2 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
12. The method of claim 2 , wherein the mitochondrial disorder is Parkinson's disease.
13. The method of claim 2 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
14. The method of claim 2 , wherein the mitochondrial disorder is Huntington's Disease.
15. The method of claim 3 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
16. The method of claim 3 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
17. The method of claim 3 , wherein the mitochondrial disorder is Parkinson's disease.
18. The method of claim 3 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
19. The method of claim 3 , wherein the mitochondrial disorder is Huntington's Disease.
20. The method of claim 2 , wherein the one or more compounds are the sole active pharmaceutical agent or agents in the composition.
21. The method of claim 3 , wherein the compound is the sole active pharmaceutical agent in the composition.
22. The method of claim 12 , wherein the one or more compounds are the sole active pharmaceutical agent or agents in the composition.
23. The method of claim 14 , wherein the one or more compounds are the sole active pharmaceutical agent or agents in the composition.
24. The method of claim 17 , wherein the compound is the sole active pharmaceutical agent in the composition.
25. The method of claim 19 , wherein the compound is the sole active pharmaceutical agent in the composition.
26. The method of claim 2 , wherein the method consists of administering the composition to the subject.
27. The method of claim 3 , wherein the method consists of administering the composition to the subject.
28. The method of claim 12 , wherein the method consists of administering the composition to the subject.
29. The method of claim 14 , wherein the method consists of administering the composition to the subject.
30. The method of claim 17 , wherein the method consists of administering the composition to the subject.
31. The method of claim 19 , wherein the method consists of administering the composition to the subject.
32. A method of treating a mitochondrial disorder, comprising administering to a subject suffering from the mitochondrial disorder a composition comprising a therapeutically effective amount of one or more compounds of the formula:
where R 11 , R 12 , and R 13 are independently selected from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , and R 13 is H, then at least one of the other two substituents is neither H nor methyl; and all stereoisomers, and mixtures of stereoisomers thereof;
wherein the one or more compounds are the sole active pharmaceutical agent or agents used to treat the mitochondrial disorder;
and wherein the mitochondrial disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); Parkinson's disease; amyotrophic lateral sclerosis (ALS); and Huntington's Disease.
33. The method of claim 32 , wherein the one or more compounds are selected from compounds of the formula:
and all stereoisomers, and mixtures of stereoisomers thereof.
34. The method of claim 32 , wherein the one or more compounds is the compound:
35. The method of claim 33 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
36. The method of claim 33 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
37. The method of claim 33 , wherein the mitochondrial disorder is Parkinson's disease.
38. The method of claim 33 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
39. The method of claim 33 , wherein the mitochondrial disorder is Huntington's Disease.
40. The method of claim 34 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
41. The method of claim 34 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
42. The method of claim 34 , wherein the mitochondrial disorder is Parkinson's disease.
43. The method of claim 34 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
44. The method of claim 34 , wherein the mitochondrial disorder is Huntington's Disease.
45. A method of treating a mitochondrial disorder, comprising administering to a subject suffering from the mitochondrial disorder a composition comprising a therapeutically effective amount of one or more compounds of the formula:
where R 11 , R 12 , and R 13 are independently selected from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , or R 13 is H, then at least one of the other two substituents is neither H nor methyl; and all stereoisomers, and mixtures of stereoisomers thereof;
and wherein the mitochondrial disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); and amyotrophic lateral sclerosis (ALS).
46. The method of claim 45 , wherein the one or more compounds are selected from compounds of the formula:
and all stereoisomers, and mixtures of stereoisomers thereof.
47. The method of claim 45 , wherein the one or more compounds is the compound:
48. The method of claim 46 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
49. The method of claim 46 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
50. The method of claim 46 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
51. The method of claim 47 , wherein the mitochondrial disorder is Friedreich's Ataxia (FA).
52. The method of claim 47 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).
53. The method of claim 47 , wherein the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).