An inherited deficiency of the X-linked hepatic enzyme omithine transcarbamylase (OTC) leads to life threatening episodes of hyperammonemia. Male infants who survive hyperammonemic coma have a high incidence (75%) of later manifesting developmental disabilities, especially if coma lasts more than 72 hours. An adenoviral vector containing normal mouse OTC cDNA was used to study the biochemical and clinical consequences of liver-directed gene therapy in a murine model, the sparse fur (spf/Y) mouse, which has 10-15% normal OTC activity. Acute hyperammonemia, similar to that observed in OTC deficient patients, was simulated in spf/Y mice following intraperitoneal injection of 10 mmol/kg NH4Cl (i.e., nitrogen challenge); animals developed ataxia, seizures, and frequently coma and death within 20 minutes of nitrogen challenge. Biochemical abnormalities included accumulation in plasma of aspartate, alanine, and glutamate. Under the same conditions, congenic normal mice remained clinically asymptomatic without changes in plasma amino acids. Intravenous injection of OTC containing adenoviral vector into spf/Y mice led to normalization of enzyme activity in liver and prevention of the accumulation of plasma amino acids. Furthermore, it spared the animals clinical sequelae following nitrogen challenge. Prevention or amelioration of biochemical and clinical abnormalities following the nitrogen challenge was evident as early as 24 hours after gene transfer. Levels returned to pre-therapy conditions by 1 month. This study demonstrates the clinical efficacy of liver-directed gene therapy in preventing acute hyperammonemia in an authentic animal model of OTC deficiency. It suggests that adenoviral mediated intravenous gene therapy may prove effective therapy for hyperammonemic coma in children with inherited urea cycle disorders and lead to improved neurodevelopmental outcome.
