Data di Pubblicazione:
2023
Citazione:
LIVER FIBROSIS IMPAIRS HEPATOCYTE TRANSDUCTION BY AAV VECTORS / G. Bruno ; tutor: Dr. Pasquale Piccolo (Telethon Institute of Genetic and Medicine (TIGEM), Naples, Italy) ; internal supervisor: Prof. Alberto Auricchio (Dept. of Advanced Biomedicine, “Federico II” University, Naples, Italy; Telethon Institute of Genetic and Medicine (TIGEM), Naples, Italy) ; external supervisor: Prof. Leszek Lisowski (Faculty of Medicine and Health, University of Sidney, Australia; Children’s Medical Research Institute (CMRI), Westmead, Australia). Dipartimento di Oncologia ed Emato-Oncologia, 2023 Mar 02. 34. ciclo, Anno Accademico 2022.
Abstract:
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.
Tipologia IRIS:
Tesi di dottorato
Keywords:
AAV ; gene therapy ; liver ; liver gene therapy ; liver fibrosis
Elenco autori:
G. Bruno
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