Compositions and Methods for the Treatment of Fatty Acid Metabolism Disorders

Abstract

Compositions and methods for inhibiting, treating, and/or preventing fatty acid metabolism disorders, particularly fatty acid oxidation disorders, in a subject are provided.

What is claimed is: 
     
         1 . A method for treating a fatty acid oxidation disorder in a subject, said method comprising administering at least one S-nitrosylating agent to said subject. 
     
     
         2 . The method of  claim 1 , wherein said fatty acid oxidation disorder is selected from the group consisting of very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD), short chain acyl-CoA dehydrogenase deficiency (SCADD), medium/short chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (M/SCHADD), multiple acyl-CoA dehydrogenase deficiency (MADD), mitochondrial trifunctional protein deficiency, short chain 3-ketoacyl-CoA thiolase deficiency (SKATD), medium chain 3-ketoacyl-CoA thiolase deficiency (MCKATD), 2,4-dienoyl-CoA reductase deficiency, and glutaric acidemia type II (GA-II). 
     
     
         3 . The method of  claim 2 , wherein said fatty acid oxidation disorder is VLCADD. 
     
     
         4 . The method of  claim 1 , wherein said S-nitrosylating agent is selected from the group consisting of nitrated fatty acid or triglyceride, acidic nitrite, nitrosyl chloride, alkyl nitrate, ethyl nitrite, amyl nitrite, glutathione (GSH), glutathione oligomer, S-nitrosoglutathione (GSNO), S-nitrosocysteinyl glycine, S-nitrosocysteine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, nitroglycerine, nitroprusside, nitric oxide, S-nitrosohemoglobin, S-nitrosoalbumin, 5-nitroso-N-acetylpenicillamine, S-nitroso-gamma-methyl-L-homocysteine, 5-nitroso-L-homocysteine, S-nitroso-gamma-thio-L-leucine, S-nitroso-delta-thio-L-leucine, S-nitrosoalbumin, and pharmaceutically acceptable salts thereof. 
     
     
         5 . The method of  claim 4 , wherein said S-nitrosylating agent is a triglyceride wherein one or two fatty acid chains have been replaced with nitrate, nitroso, or nitro. 
     
     
         6 . The method of  claim 5 , wherein said S-nitrosylating agent is a triglyceride wherein one or two fatty acid chains have been replaced with nitrate. 
     
     
         7 . The method of  claim 5 , wherein the fatty acids of the triglyceride comprise at least 7 carbons. 
     
     
         8 . The method of  claim 7 , wherein the fatty acids of the triglyceride are 7 to 11 carbons in length. 
     
     
         9 . The method of  claim 4 , wherein said S-nitrosylating agent is selected from the group consisting of 1,3-diheptanoin-2-mononitrate; 1,2-diheptanoin-3-mononitrate; 2,3-diheptanoin-1-mononitrate; 1,3-dinitrate-2-heptanoin; 1,2-dinitrate-3-heptanoin; and 2,3-dinitrate-1-heptanoin. 
     
     
         10 . The method of  claim 4 , wherein said S-nitrosylating agent is a mononitrated-diheptanoin. 
     
     
         11 . The method of  claim 5 , further comprising the administration of S-nitroso-N-acetyl-cysteine (SNO-NAC). 
     
     
         12 . The method of  claim 1 , further comprising the administration of at least one other therapeutic agent for the treatment of the fatty acid oxidation disorder. 
     
     
         13 . The method of  claim 12 , wherein said other therapeutic agent is triheptanoin or bezafibrate. 
     
     
         14 . The method of  claim 1 , further comprising diagnosing a fatty acid oxidation disorder in said subject prior to administration of said S-nitrosylating agent. 
     
     
         15 . The method of  claim 14 , wherein said diagnosis comprises:
 a) obtaining a biological sample from said subject;   b) determining the enzymatic activity of the very long-chain acyl-coenzyme A dehydrogenase (VLCAD) in said sample; and   c) comparing the amount of VLCAD enzymatic activity determined in step b) to the amount of VLCAD enzymatic activity in a corresponding biological sample from a healthy subject, wherein a decrease in the VLCAD enzymatic activity in the biological sample from the subject compared to the healthy subject is indicative of a fatty acid oxidation disorder in said subject.   
     
     
         16 . The method of  claim 14 , wherein the diagnosis comprises determining the presence of a mutation in a the very long-chain acyl-coenzyme A dehydrogenase (VLCAD) encoding nucleic acid molecule in a biological sample obtained from said subject, wherein the presence of a mutation in the VLCAD encoding nucleic acid molecule is indicative of a fatty acid oxidation disorder in said subject.