LIVER FIBROSIS IMPAIRS HEPATOCYTE TRANSDUCTION BY AAV VECTORS

Adeno-associated viral vectors (AAVs) are the most promising tools for liver directed gene therapy. However, integrity of hepatic architecture has been considered pre-requisite for efficient gene delivery and clinical studies have been addressed toward patients with no or negligible hepatic damage and fibrosis. Preliminary evidence suggests that AAV-mediated gene transfer to hepatocytes may be hampered by liver fibrosis, but knowledge about AAV vector interactions with fibrotic livers is still very limited. In the present study, we investigated hepatocyte transduction and biodistribution of AAV8-based vectors, commonly used in liver-directed gene therapy clinical trials, in the context of liver fibrosis. Analysis of three mouse models of induced and genetic liver fibrosis revealed that fibrotic livers are transduced less efficiently by AAV8 and this results from reduced vector uptake by the liver. Moreover, liver fibrosis altered blood vector clearance and vector biodistribution in extra-hepatic organs. Overall, these findings demonstrated that liver fibrosis impairs AAV-mediated gene transfer to hepatocytes and highlight the relevance of the limitations posed by liver fibrosis to efficient and safe gene transfer.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2023

Author dc:creator

• BRUNO, GEMMA

Contributors dc:contributor

• tutor: Dr. Pasquale Piccolo (Telethon Institute of Genetic and Medicine (TIGEM)
• Naple
• Italy) ; internal supervisor: Prof. Alberto Auricchio (Dept. of Advanced Biomedicine
• “Federico II” University
• Italy; Telethon Institute of Genetic and Medicine (TIGEM)
• Italy) ; external supervisor: Prof. Leszek Lisowski (Faculty of Medicine and Health
• University of Sidney
• Australia; Children’s Medical Research Institute (CMRI)
• Westmead
• Australia)
• G. Bruno

• AAV
• gene therapy
• liver
• liver gene therapy
• liver fibrosis
• Settore MED/03 - Genetica Medica

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/bruno-gemma_phd2023-03-02
10.13130/bruno-gemma_phd2023-03-02

OAI identifier oai:identifier

oai:air.unimi.it:2434/955885