547. Improvement of Liver Gene Transfer by First and Third Generation Adenoviral Vectors

Recombinant adenoviruses are among the most extensively used vectors in gene therapy studies. To optimize adenovirus-mediated liver transduction we have studied the effect of the route of administration using first and third generation adenovirus vectors. We compared the local delivery of those vectors, using direct intrahepatic injection (IH), and the systemic administration via tail vein (IV). IH injection of first generation adenovirus resulted in a three-fold increase transgene expression when a high dose of virus was administered. More importantly when a relatively low dose of virus was used, IV administration resulted in no detectable protein expression while IH administration resulted in high levels of protein in serum. Significant differences in the kinetic and location of protein expression were observed depending on the route, IH injection resulted in a faster protein expression which localized to the site of injection, compared to widespread liver expression following IV administration. A 3 fold increase in the level of protein expression was also obtained after IH injection of a helper-dependent adenovirus expressing hIL-12 (HD-hIL12). Furthermore, IH injection using a HD-Ad carrying murine IL12 (HD-mIL12) correlated with the improvement of its antitumoral efficacy in a murine tumor model. Macrophage depletion experiments using clodronate loaded-liposomes showed that IH injection partially circumvent macrophage phagocytic activity. Interestingly, the administration of empty liposomes increases transgene expression without macrophage depletion regardless of the route of administration. In summary, our study describes two ways to improve liver transduction using adenovirus-based vectors: 1, direct liver injection of the adenovirus 2, administration of empty liposomes prior to virus injection.