905. Hydrodynamic Injection of Helper-Dependent Adenoviral Vectors Increases Liver Transduction Efficiency and Decreases Acute Inflammatory Response

Abstract

Hydrodynamic injection of helper-dependent adenoviral vectors (HDAd) in mice results in increased hepatic transduction resulting in higher levels of long-term transgene expression compared to conventional injection. Furthermore, hydrodynamic injection resulted in reduced splenic and pulmonary transduction and reduced serum levels of the proinflammatory cytokines IL-6 and IL-12. Interestingly, hydrodynamic injection does not appear to alter Kupffer cell uptake of the vector compared to conventional injection. Taken together, these results strongly suggest that hepatic transduction by HDAd, at least alone, does not necessarily provoke a severe innate inflammatory response, but that systemic vector dissemination may play a major role in the severity of the innate inflammatory response. These results further suggest that the safety and efficacy of HDAd-mediated, liver-directed gene therapy may be improved if the vector could be preferentially, if not exclusively, targeted to hepatocytes.