Liver fibrosis negatively impacts in vivo gene transfer to murine hepatocytes

Chiara Simoni, Justine Nozi, Francesco Starinieri, Tiziana La Bella, Elisabetta Manta, Camilla Negri, Mauro Biffi, Rossana Norata, Martina Rocchi, Francesca Sanvito, Giuseppe Ronzitti, Elena Barbon () and Alessio Cantore ()
Additional contact information
Chiara Simoni: IRCCS San Raffaele Scientific Institute
Justine Nozi: Généthon
Francesco Starinieri: IRCCS San Raffaele Scientific Institute
Tiziana La Bella: Généthon
Elisabetta Manta: IRCCS San Raffaele Scientific Institute
Camilla Negri: IRCCS San Raffaele Scientific Institute
Mauro Biffi: IRCCS San Raffaele Scientific Institute
Rossana Norata: IRCCS San Raffaele Scientific Institute
Martina Rocchi: IRCCS San Raffaele Scientific Institute
Francesca Sanvito: IRCCS San Raffaele Scientific Institute
Giuseppe Ronzitti: Généthon
Elena Barbon: IRCCS San Raffaele Scientific Institute
Alessio Cantore: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Liver fibrosis occurs in several genetic and acquired disease conditions, leading to alterations of the tissue and metabolism, which may adversely affect viral vector-mediated gene therapy. Here, we assessed the impact of liver fibrosis on in vivo gene transfer to hepatocytes mediated by lentiviral vectors or adeno-associated viral vectors. We exploited two chemically induced fibrosis mouse models characterized by tissue damage in different areas 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 liver fibrosis. We report a general negative influence of liver fibrosis on hepatocyte transduction and alteration of the vector distribution within the liver lobule, with different outcomes according to the viral vector used and the state of the liver at the time of vector administration. This study bears implications for future developments and applications of in vivo liver-directed gene therapy.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57383-8

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DOI: 10.1038/s41467-025-57383-8

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