METHODS OF TREATING ORGANIC ACIDEMIAS
The present disclosure relates to methods of treating organic acidemias. In some embodiments, the methods comprise reducing propionyl-CoA, isovaleryl-CoA and methylmalonyl-CoA production, and various related metabolites, in a subject in need thereof.
1 . A method of treating an organic acidemia in a subject in need thereof, comprising:
administering 2,2-dimethylbutyric acid, or a pharmaceutically acceptable salt or ester thereof, to the subject,
thereby reducing at least one metabolite that would otherwise accumulate in an organic acidemia patient, thereby treating the organic acidemia.
2 . The method of claim 1 , wherein the organic acidemia is propionic acidemia.
3 . The method of claim 1 , wherein the organic acidemia is methylmalonic acidemia.
4 . A method of treating propionic acidemia in a subject in need thereof, comprising:
administering 2,2-dimethylbutyric acid, or a pharmaceutically acceptable salt or ester thereof,
thereby reducing levels of at least one metabolite that would otherwise accumulate in a propionic acidemia patient, thereby treating propionic acidemia in the subject.
5 . A method of treating methylmalonic acidemia in a subject in need thereof, comprising:
administering 2,2-dimethylbutyric acid, or a pharmaceutically acceptable salt or ester thereof,
thereby reducing levels of at least one metabolite that would otherwise accumulate in a methylmalonic acidemia patient, thereby treating methylmalonic acidemia in the subject.
6 . A method of reducing propionyl-CoA or methylmalonyl-CoA production in a subject in need thereof, comprising administering an effective amount 2,2-dimethylbutyric acid, or the pharmaceutically acceptable salt or ester thereof, to the subject.
7 . The method of any one of claims 1 - 6 , wherein 2,2-dimethylbutyric acid, or the pharmaceutically acceptable salt or ester thereof, is present in a pharmaceutical composition.
8 . The method of claim 7 , wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient and an effective amount of 2,2-dimethylbutyric acid, or an ester or pharmaceutically acceptable salt thereof.
9 . The method of any of claims 1 - 8 , wherein the at least one metabolite comprises propionic acid, 3-hydroxypropionic acid, methylcitrate, glycine, or propionylcarnitine, or combinations thereof.
10 . The method of any of claims 1 - 9 , wherein at least one metabolite comprises 2-ketoisocaproate, isovaleryl-CoA, 3-methylcrotonyl-CoA, 3-methylglutaconyl-CoA, 3-OH-3-methylglutaryl-CoA, 2-keto-3-methylvalerate, 2-methylbutyryl-CoA, tiglyl-CoA, 2-methyl-3-OH-butyryl-CoA, 2-methyl-acetoacetyl-CoA, 2-ketoisovalerate, isobutyryl-CoA, methylacrylyl-CoA, 3-OH-isobutyryl-CoA, 3-OH-isobutyrate, methylmalonic semialdehyde, propionyl-CoA, or methylmalonyl-CoA, or combinations thereof.
11 . The method of any of claims 1 - 10 , wherein the at least one metabolite is reduced by an amount ranging from at least about 1% to about 100%.
12 . A method of treating a metabolic disorder, comprising administering 2,2-dimethylbutyric acid, or an ester or pharmaceutically acceptable salt thereof.
13 . The method of claim 12 , wherein the metabolic disorder is selected form the group consisting of propionic acidemia, methylmalonic acidemia, mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (OMIM 616277), 3-hydroxyisobutyryl-CoA hydrolase deficiency (OMIM 250620), 3-hydroxyisobutyrate dehydrogenase deficiency, methylmalonate-semialdehyde dehydrogenase deficiency (OMIM 614105), 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (OMIM 300438), or 3-methylacetoacetyl-CoA thiolase deficiency (OMIM 203750), 3-hydroxy-3-methylglutaric aciduria and combinations thereof.
14 . The method of claim 9 , wherein the at least one metabolite is reduced by an amount in the range of from about 1% to about 100%.
15 . The method of claim 1 , wherein the organic acidemia is isovaleric acidemia.
16 . The method of any one of claims 1 - 15 , wherein the pharmaceutically acceptable salt of 2,2-dimethylbutyric acid is a sodium salt.
17 . A method of treating an organic acidemia in a subject in need thereof, comprising: administering a compound of Formula (IA), or an ester or pharmaceutically acceptable salt thereof, to the subject,
wherein:
each of R 1 , R 2 and R 3 is independently H, alkyl, carbocyclyl, or carbocyclylalkyl, provided that at least one of R 1 , R 2 and R 3 is not H; and
R 4 is H alkyl, or carnitine.
18 . The method of claim 17 , wherein each of R 1 , R 2 and R 3 is independently H, alkyl, or carbocyclyl, provided that at least one of R 1 , R 2 and R 3 is not H.
19 . The method of claim 17 or 18 , wherein at least one of R 1 , R 2 and R 3 is alkyl.
20 . The method of claim 17 or 18 , wherein at least two of R 1 , R 2 and R 3 are alkyl.
21 . The method of any one of claims 17 - 20 , wherein the alkyl is a C 1-6 alkyl.
22 . The method of any one of claims 17 - 21 , wherein the alkyl is selected from the group consisting of methyl, ethyl, in-propyl, n-butyl, and t-butyl.
23 . The method of any one of claims 17 - 22 , wherein one of R 1 , R 2 and R 3 is carbocyclyl.
24 . The method of any one of claims 17 - 23 , wherein the carbocyclyl is a cyclopropyl.
25 . The method of any one of claims, 17 - 22 , wherein R 1 is H, R 2 is H, methyl, ethyl, or n-propyl, and R 3 is ethyl, n-propyl, t-butyl, or cyclopropyl.
26 . The method of any one of claims 17 - 22 , wherein R 1 and R 2 are methyl, and R 3 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, and cyclopropyl.
27 . The method of any one of claims 17 - 22 , wherein R 1 and R 2 are methyl, and R 3 is ethyl.
28 . The method of any one of claims 17 - 27 , wherein R 4 is alkyl.
29 . The method of claim 28 , wherein the alkyl is a C 1-4 alkyl.
30 . The method of claim 29 , wherein the C 1-4 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, or t-butyl.
31 . The method of any one of claims 17 - 27 , wherein R 4 is H.
32 . A method of treating a patient with elevated propionyl-CoA or methylmalonyl-CoA with a combination of 2,2-dimethylbutyric acid or pharmaceutically acceptable salt thereof in combination with carnitine
33 . A method of treating a patient that has had a liver, kidney or liver and kidney transplant with 2,2-dimethylbutryic acid or pharmaceutically acceptable salt thereof.
34 . A method of treating a patient with 2,2-dimethylbutryic acid or pharmaceutically acceptable salt thereof before, after or in combination with mRNA-3927, mRNA-3704 or LB001.
35 . A method of treating a patient with 2,2-dimethylbutryic acid or pharmaceutically acceptable salt thereof before, after or during AAV delivered gene therapy that is designed to replace PCC or MUT.
36 . A method of treating a patient with 2,2-dimethylbutryic acid or pharmaceutically acceptable salt thereof before, after or during a gene therapy treatment that is designed to replace PCC or MUT.