Gene transfer into the liver of nonhuman primates with E1-deleted recombinant adenoviral vectors: Safety of readministration

Preclinical studies were designed to investigate the safety of recombinant adenoviruses infused into the portal vein of adult rhesus monkeys, as well as the safety and efficacy of readministration of these agents. The vectors used were recombinant adenoviruses, the Fl region of which was replaced wi th a marker gene expression cassette. Four 3- to 5-kg rhesus monkeys underw ent portal vein cannulation, and infusion of escalating doses of recombinan t first-generation vector, Serial sequential liver biopsies were performed, and necropsies were performed out to 14 months. X-Gal histochemical analys is of the liver showed evidence of dose-dependent increased gene transfer t hroughout the liver, Quantitative analysis of histopathology showed that po rtal inflammation was also present in transduced livers, and occurred in a dose-dependent manner. Severe toxicity, including mortality, was noted at t he highest dose of vector. Readministration of a second vector was associat ed with the same degree of toxicity as the first vector, but prompted a muc h more vigorous neutralizing antibody response. The data suggest that intra portal administration and readministration of recombinant adenoviral E1-del eted vectors are feasible and safe, Vector administration at the highest do se (1 x 10(13) particles/kg) was associated with severe clinical and bioche mical toxicity, and significant gene expression was associated with transam initis, Readministration of vector is safe, but gene transfer is limited by the presence of neutralizing antibody.