ADENOVIRUS-MEDIATED HEPATIC GENE-TRANSFER IN MICE - COMPARISON OF INTRAVASCULAR AND BILIARY ADMINISTRATION

Recombinant adenoviruses have received much attention as a potential v ector for gene therapy because of their ability to transduce many cell types with high efficiencies in vivo, After intravenous infusion, the majority of the vector is found in hepatocytes, but vector DNA is fou nd to varying degrees in other tissues, In an attempt to restrict aden ovirus-mediated gene transfer to the liver, we developed a microsurgic al method that allowed for vector administration directly into the bil iary tract of a mouse, We demonstrate that gene transfer was 4- to Ill -fold more restricted to the liver after biliary tract infusion than a fter intravascular infusion, Intravascular infusion of recombinant ade novirus elicits a powerful immune response that limits gene expression and the ability to readminister the vector, Biliary infusion resulted in a slightly lesser immune response as determined by the lower neutr alizing antibody titers directed against the vector compared with anim als treated by intravascular infusion, There was no difference in the persistence of gene expression, suggesting a similar cell-mediated imm une response against the vector containing cells in animals administer ed vector by either method, As future-generation adenovirus vectors th at are safer and less immunogenic become available, the more liver spe cific gene transfer via the biliary tract may offer advantages over in travenous infusion for hepatic gene therapy.