Myocyte-mediated arginase expression controls hyperargininemia but not hyperammonemia in arginase-deficient mice

Mol Ther. 2014 Oct;22(10):1792-802. doi: 10.1038/mt.2014.99. Epub 2014 Jun 3.


Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia that cause neurological impairment and growth retardation. We previously developed a neonatal mouse adeno-associated viral vector (AAV) rh10-mediated therapeutic approach with arginase expressed by a chicken β-actin promoter that controlled plasma ammonia and arginine, but hepatic arginase declined rapidly. This study tested a codon-optimized arginase cDNA and compared the chicken β-actin promoter to liver- and muscle-specific promoters. ARG1(-/-) mice treated with AAVrh10 carrying the liver-specific promoter also exhibited long-term survival and declining hepatic arginase accompanied by the loss of AAV episomes during subsequent liver growth. Although arginase expression in striated muscle was not expected to counteract hyperammonemia, due to muscle's lack of other urea cycle enzymes, we hypothesized that the postmitotic phenotype in muscle would allow vector genomes to persist, and hence contribute to decreased plasma arginine. As anticipated, ARG1(-/-) neonatal mice treated with AAVrh10 carrying a modified creatine kinase-based muscle-specific promoter did not survive longer than controls; however, their plasma arginine levels remained normal when animals were hyperammonemic. These data imply that plasma arginine can be controlled in arginase deficiency by muscle-specific expression, thus suggesting an alternative approach to utilizing the liver for treating hyperargininemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / genetics*
  • Arginase / metabolism
  • Cell Line
  • Codon
  • Dependovirus / genetics
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation*
  • Genetic Vectors / genetics
  • Hepatocytes / metabolism
  • Humans
  • Hyperammonemia / genetics*
  • Hyperammonemia / metabolism
  • Hyperargininemia / genetics*
  • Hyperargininemia / metabolism
  • Hyperargininemia / mortality
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Cells / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Myoblasts, Cardiac / metabolism
  • Organ Specificity / genetics
  • Promoter Regions, Genetic


  • Codon
  • Arginase