PROLONGED METABOLIC CORRECTION IN ADULT ORNITHINE TRANSCARBAMYLASE-DEFICIENT MICE WITH ADENOVIRAL VECTORS

A murine model of ornithine transcarbamylase (OTC) deficiency was used in this study to evaluate the efficacy of recombinant adenoviruses fo r correcting the metabolic defect in liver. Recombinant adenoviruses d eleted in E1 and containing a human OTC cDNA expressed little function al OTC enzyme in vivo and had no observable impact on the underlying m etabolic abnormalities of the OTC-deficient mouse (i.e. elevated urina ry orotate and serum glutamine). E1-deleted vectors were improved thro ugh the use of the strong constitutive promoter from cytomegalovirus d riving the normal murine homolog of OTC cDNA and the ablation of E2a w ith a temperature-sensitive mutation. Infusion of this improved vector into the mouse model was associated with a complete normalization of liver OTC enzyme activity that persisted for at least 2 months with co mplete but transient correction in serum glutamine and urine erotic ac id. These studies illustrate the utility of improved adenoviral vector s in the treatment of liver metabolic disease.