Methods of modulation of branched chain acids and uses thereof

Abstract

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.

What is claimed is: 
     
         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.