ADENOVIRUS-MEDIATED IN-VIVO GENE-TRANSFER RAPIDLY PROTECTS ORNITHINE TRANSCARBAMYLASE-DEFICIENT MICE FROM AN AMMONIUM CHALLENGE

The purpose of this study was to determine the time of onset, duration , and the efficacy of in vivo gene transfer in protecting the ornithin e transcarbamylase deficient spf/Y mouse from an acute ammonium challe nge. The animals were challenged with ammonia (10 mmol/kg NH4Cl) 1, 2, 7, 14, or 28 d after the administration of a recombinant adenoviral c onstruct deleted in El and with a temperature sensitive mutation in E2 . Although there was no protection with the control LacZ virus, the or nithine transcarbamylase (OTC)-containing vector provided partial prot ection from both behavioral symptoms (ataxia, seizures, and abnormal r esponse to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h. M ortality was also decreased. Animals receiving the vector 7 and 14 d b efore the ammonium load were also protected, whereas those treated 28 d before the challenge were not. OTC enzyme activity in liver of untre ated spf/Y mice was 5% of control C3H mice. After gene transfer, activ ity 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 administratio n and provides protection against an acute metabolic insult for at lea st 2 wk.