Liver fibrosis negatively impacts in vivo gene transfer to hepatocytes

Liver fibrosis is a pathological process occurring in several genetic and acquired disease conditions. The fibrosis-related alterations of the liver tissue and hepatic cell metabolism may negatively affect therapeutic approaches targeting the liver. Among these, viral-vector-mediated gene transfer to the liver showed clinical efficacy and safety as a treatment for inherited diseases due to defects in hepatic function. Here we assessed the impact of liver fibrosis on gene transfer to hepatocytes mediated by lentiviral vectors (LV) or adeno-associated viral (AAV) vectors administered systemically. We exploited two chemically induced fibrosis mouse models, characterized by tissue damage in the area near the portal vein (peri-portal) or the central vein (peri-central) of the liver lobule. Moreover, we used Abcb11 ^–/– and Agl ^−/− mice, recapitulating features of inherited cholestasis and glycogen storage disease, as representative models of genetic disorders characterized by peri-portal fibrosis. We report that both peri-central and peri-portal fibrosis partially inhibited LV-mediated hepatocyte gene transfer, while the efficiency of AAV-vector-mediated gene transfer was reduced in the case of preexisting peri-portal fibrosis. Gene transfer by both vectors was not altered by the minimal peri-portal fibrosis present In Agl ^−/− mice. This work provides evidence that the presence of significant hepatic fibrosis generally reduced transduction efficiency, with different outcomes according to the vector used and the state of the liver at the time of vector administration. Overall, this study has relevant implications for future developments and applications of liver-directed gene therapy.