Two key challenges for effective adenovirus-mediated liver gene therapy: innate immune responses and hepatocyte-specific transduction.

Adenovirus (Ad) are valuable vectors for liver gene therapy because of their intrinsic ability to transduce hepatocytes following intravenous administration. However, the effective application of these vectors, including helper-dependent Ad unable to trigger viral gene expression, for liver gene therapy in humans has been limited due to several obstacles. First, their high immunogenicity triggers a complex immune response, both innate and adaptive, that leads to hepatocyte destruction, reducing the duration of transgene expression. This high immunogenicity also induces a long lasting cellular and humoral immunity that impairs subsequent re-administration. Second, Ad vectors transduce not only hepatocytes but also other cell types from the liver or other organs. This Ad vector dissemination contributes to their toxicity and immunogenicity, further reducing the effective period of transgene expression. A better understanding of the interactions between Ad vectors and their host underlying the acute liver toxicity and hepatocyte transduction is required to improve the efficacy and duration of gene delivery in vivo. The aim of this review is to discuss insights into the cellular and molecular mechanisms involved in Ad vector-mediated innate immune responses. Current advances in the knowledge of Ad liver tropism and the influence of blood components on Ad vector uptake by the liver will be discussed. Finally, different approaches developed to minimize Ad vector toxicity, optimize delivery and increase transgene expression will be summarized. The full potential of Ad vectors will only be reached when their immunogenicity is abolished and hepatocyte-specific transduction achieved.