Impact of liver fibrosis on AAV-mediated gene transfer to mouse hepatocytes

Rosa Ferriero, Gemma Bruno, Agnese Padula, Simone Pisano, Iolanda Boffa, Marco Gargaro, Teresa Imperatore, Maria Battipaglia, Silvia Vivenzio, Claudia Perna, Edoardo Nusco, Luigi Ferrante, Adrian Westhaus, Maddison Knight, Giorgia Manni, Severo Campione, Evaristo Napoli, Elena Polishchuk, Roman Polishchuk, Orlando Paciello, Nicola Brunetti-Pierri, Leszek Lisowski, Francesca Fallarino and Pasquale Piccolo ()
Additional contact information
Rosa Ferriero: Telethon Institute of Genetics and Medicine (TIGEM)
Gemma Bruno: Telethon Institute of Genetics and Medicine (TIGEM)
Agnese Padula: Telethon Institute of Genetics and Medicine (TIGEM)
Simone Pisano: Telethon Institute of Genetics and Medicine (TIGEM)
Iolanda Boffa: Telethon Institute of Genetics and Medicine (TIGEM)
Marco Gargaro: University of Perugia
Teresa Imperatore: Telethon Institute of Genetics and Medicine (TIGEM)
Maria Battipaglia: Telethon Institute of Genetics and Medicine (TIGEM)
Silvia Vivenzio: Telethon Institute of Genetics and Medicine (TIGEM)
Claudia Perna: Telethon Institute of Genetics and Medicine (TIGEM)
Edoardo Nusco: Telethon Institute of Genetics and Medicine (TIGEM)
Luigi Ferrante: Telethon Institute of Genetics and Medicine (TIGEM)
Adrian Westhaus: The University of Sydney
Maddison Knight: The University of Sydney
Giorgia Manni: University of Perugia
Severo Campione: Cardarelli Hospital
Evaristo Napoli: “Federico II” University of Naples
Elena Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Roman Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Orlando Paciello: “Federico II” University of Naples
Nicola Brunetti-Pierri: Telethon Institute of Genetics and Medicine (TIGEM)
Leszek Lisowski: The University of Sydney
Francesca Fallarino: University of Perugia
Pasquale Piccolo: Telethon Institute of Genetics and Medicine (TIGEM)

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

Abstract: Abstract Liver fibrosis, characterized by scar tissue accumulation due to liver injury, poses significant barriers to liver-targeted gene therapy. Current clinical trials exclude patients with fibrosis, as intact liver architecture is considered essential for efficient and safe adeno-associated viral vector (AAV)-mediated gene delivery. Here, we show that liver fibrosis reduces the efficiency of hepatocyte transduction by AAV8 vectors across three mouse models with diverse fibrotic patterns. This inefficiency stems primarily from decreased vector uptake by the liver rather than loss of vector genomes due to hepatocyte turnover. Additionally, fibrosis alters blood vector clearance and redistributes AAV particles to extra-hepatic organs, such as spleen, lung, and kidney. At the cellular level, fibrosis decreases AAV genome content in hepatocytes while increasing it in non-parenchymal liver cells and splenic immune cells. Importantly, the capsid variant AAV-KP1 retains transduction efficiency in fibrotic livers, highlighting its potential for expanding gene therapy applications to fibrotic diseases.

Date: 2025
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DOI: 10.1038/s41467-025-57382-9

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