Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector

Mol Ther. 2009 Jul;17(7):1155-63. doi: 10.1038/mt.2009.65. Epub 2009 Apr 14.


Neonatal gene therapy has the potential to ameliorate abnormalities before disease onset. Our gene knockout of arginase I (AI) deficiency is characterized by increasing hyperammonemia, neurological deterioration, and early death. We constructed a helper-dependent adenoviral vector (HDV) carrying AI and examined for correction of this defect. Neonates were administered 5 x 10(9) viral particles/g and analyzed for survival, arginase activity, and ammonia and amino acids levels. The life expectancy of arg(-/-) mice increased to 27 days while controls died at 14 days with hyperammonemia and in extremis. Death correlated with a decrease in viral DNA/RNA per cell as liver mass increased. Arginase assays demonstrated that vector-injected hepatocytes had ~20% activity of heterozygotes at 2 weeks of age. Hepatic arginine and ornithine in treated mice were similar to those of saline-injected heterozygotes at 2 weeks, whereas ammonia was normal. By 26 days, arginase activity in the treated arg(-/-) livers declined to <10%, and arginine and ornithine increased. Ammonia levels began increasing by day 25, suggesting the cause of death to be similar to that of uninjected arg(-/-) mice, albeit at a later time. These studies demonstrate that the AI deficient newborn mouse can be temporarily corrected and rescued using a HDV.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Amino Acids / metabolism
  • Ammonia / metabolism
  • Animals
  • Animals, Newborn
  • Arginase / genetics*
  • Arginase / metabolism
  • Arginase / physiology
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics*
  • Hyperammonemia / therapy*
  • Hyperargininemia / therapy*
  • Mice
  • Mice, Knockout


  • Amino Acids
  • Ammonia
  • Arginase