METHODS OF MODULATION OF BRANCHED CHAIN ACIDS AND USES THEREOF
A method of modulating plasma levels of branched chain amino acids and branched chain alpha-keto acids is disclosed, wherein an ammonia scavenger compound or a salt thereof, for example phenylbutyrate or an even numbered congener thereof or a salt thereof, is administered to an individual in need thereof. In various methods, a decrease in plasma levels of branched chain amino acids and branched chain alpha-keto acids is effected to treat individuals suffering from an inborn error in metabolism of amino acids, such as Maple Syrup Urine Disease, for example.
1 . A method of treating an individual having a metabolic disorder from an inborn error in metabolism of one or more branched chain amino acids, comprising administering to the individual a therapeutically effective amount of a composition comprising one or more ammonia scavengers.
2 . The method of claim 1 , wherein the metabolic disorder is selected from the group consisting of maple syrup urine disease (MSUD), hypervalinemia, isobutyryl-CoA dehydrogenase deficiency,⋅beta-ketothiolase deficiency, 2-Methylbutyryl-CoA dehydrogenase deficiency, hypermethioninemia, homocystinuria, cystathioninuria, isovaleric acidemia, 3-Methylcrotonyl-CoA carboxylase deficiency, or 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, Fragile X, tuberous sclerosis, Rett syndrome, autism, diabetes, and a combination thereof.
3 . The method of claim 1 , wherein the metabolic disorder comprises an increase in blood plasma levels of branched chain amino acids and/or branched chain alpha-keto acids.
4 . The method of claim 3 , wherein the branched chain amino acid is at least one of leucine, isoleucine, and valine.
5 . The method of claim 3 , wherein the branched chain alpha-keto acid is at least one of keto-isocaproic acid, keto-methylvaleric acid, and ketoisovaleric acid.
6 . The method of claim 1 , wherein the ammonia scavenger is selected from the group consisting of phenylbutyrate, BUPHENYL® (sodium phenylbutyrate), AMMONAPS®, butyroyloxymethyl-4-phenylbutyrate, glyceryl tri-[4-phenylbutyrate] (HPN-100), esters, ethers and a combination thereof,
7 . The method of claim 1 , wherein the ammonia scavenger is the native form, a salt, an acid, and/or a prodrug of a native ammonia scavenger.
8 . The method of claim 7 , wherein the salt is the sodium salt, calcium salt, lithium salt, potassium salt, or a mixture thereof.
9 . The method of claim 1 , wherein the ammonia scavenger is at least one compound of the formula:
wherein n 0, 2, 4, 6 or 8, or a pharmaceutically acceptable salt or ester or prodrug thereof.
10 . The method of claim 1 , wherein the administration of the ammonia scavenger results in a decrease in blood plasma levels of branched chain amino acids and/or branched chain alpha-keto acids.
11 . The method of claim 1 , wherein administration of the ammonia scavenger stimulates the baseline enzymatic activity of the branched chain dehydrogenase enzyme complex protein to levels effective in achieving decreased branched chain amino acid and/or branched chain alpha-keto acid levels.
12 . The method of claim 10 , wherein the stimulation of activity is caused by a decrease in the phosphorylation of S293 and S303 residues of the E1□□ subunit of the branched chain dehydrogenase enzyme complex.
13 . The method of claim 1 , further comprising assaying for a decrease in plasma levels of at least one of said branched chain amino acids and/or assaying for a decrease in plasma levels of branched chain alpha-keto acids.
14 . A method for stimulating the baseline enzymatic activity of the branched chain dehydrogenase enzyme complex protein in an individual comprising administrating a therapeutically effective amount of one or more ammonia scavengers to the individual.
15 . The method of claim 14 , wherein the stimulation of activity is caused by a decrease in the phosphorylation of S293 and S303 residues of the E1□□ subunit of the branched chain dehydrogenase enzyme complex.
16 . The method of claim 14 , wherein the individual has an inborn error of metabolism.
17 . The method of claim 14 , wherein the individual has an accumulation of branched chain amino acids and/or branched chain alpha-keto acids in the individual's blood plasma.
18 . The method of claim 14 , wherein the ammonia scavenger is a composition selected from this list consisting of phenylbutyrate, BUPHENYL® (sodium phenylbutyrate), AMMONAPS®, butyroyloxymethyl-4-phenylbutyrate, glyceryl tri-[4-phenylbutyrate] (HPN-100), esters, ethers and a combination thereof, wherein the composition is the native form, a salt, an acid, and/or a prodrug of the native composition.
19 . The method of claim 18 , wherein the salt is the sodium salt, calcium salt, lithium salt, and/or potassium salt.
20 . The method of claim 14 , wherein the ammonia scavenger is at least one compound of the formula:
wherein n 0, 2, 4, 6 or 8, or a pharmaceutically acceptable salt or ester or prodrug thereof.
21 . The method of claim 14 , wherein the administration of the one or more ammonia scavengers comprises a decrease in blood plasma levels of branched chain amino acids and/or branched chain alpha-keto acids.