Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer

Stable gene transfer into hepatocytes has been proposed to compensate for g enetic deficiencies that affect liver function, or to deliver diffusible fa ctors into the circulation. This strategy can be achieved using retroviral vectors; however, cell division must occur. We describe a simple and reprod uctive method that enables the induction of hepatocyte replication in a con trolled fashion, thus allowing an efficient in vivo retroviral liver transd uction that is applicable to mouse models of human genetic disorders. The a pproach is based on liver susceptibility to apoptosis via the Fas/CD95 path way. We show that, 4 days following a single Fas agonist antibody (JO2) inj ection, hepatocyte replication occurs, the intensity of which is correlated with the level of the induced hepatic cytolysis, This treatment enables in vivo liver transduction, and its efficiency also correlates with the level of hepatic cytolysis. When recombinant retroviral vectors were infused int ravenously during the period of hepatocyte replication, 15.4% +/- 1.7% of t he hepatocytes were transduced, reaching up to 32.5%.