Adenovirus-mediated in vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge

Pediatr Res. 1997 Apr;41(4 Pt 1):527-34. doi: 10.1203/00006450-199704000-00012.


The purpose of this study was to determine the time of onset, duration, and the efficacy of in vivo gene transfer in protecting the ornithine transcarbamylase deficient spf/Y mouse from an acute ammonium challenge. The animals were challenged with ammonia (10 mmol/kg NH4Cl) 1, 2, 7, 14, or 28 d after the administration of a recombinant adenoviral construct deleted in E1 and with a temperature sensitive mutation in E2. Although there was no protection with the control LacZ virus, the ornithine transcarbamylase (OTC)-containing vector provided partial protection from both behavioral symptoms (ataxia, seizures, and abnormal response to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h. Mortality was also decreased. Animals receiving the vector 7 and 14 d before the ammonium load were also protected, whereas those treated 28 d before the challenge were not. OTC enzyme activity in liver of untreated spf/Y mice was 5% of control C3H mice. After gene transfer, activity was increased to near control levels through 14 d but had returned to baseline by 28 d. These studies indicate that adenovirus-mediated gene transfer confers a metabolic benefit within 24 h of administration and provides protection against an acute metabolic insult for at least 2 wk.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Ammonium Chloride*
  • Animals
  • Behavior, Animal / physiology
  • Gene Transfer Techniques*
  • Genetic Vectors*
  • Lac Operon
  • Liver / enzymology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred Strains
  • Nitrogen / metabolism
  • Ornithine Carbamoyltransferase Deficiency Disease*
  • Time Factors


  • Ammonium Chloride
  • Nitrogen