Low Incidence of Hepatocellular Carcinoma in Mice and Cats Treated with Systemic Adeno-associated Viral Vectors

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2021 Jan 21

PMID 33473358

Citations 18

Authors

Rita Ferla

Marialuisa Alliegro

Margherita DellAnno

Edoardo Nusco

John M Cullen

Stephanie N Smith

Tyra G Wolfsberg

Patricia ODonnell

Ping Wang

Anh-Dao Nguyen

Randy J Chandler

Zelin Chen

Shawn M Burgess

Charles H Vite

Mark E Haskins

Charles P Venditti

Alberto Auricchio

Affiliations

Soon will be listed here.

Abstract

Adeno-associated viral (AAV) vectors have emerged as the preferred platform for gene transfer because of their combined efficacy and safety. However, insertional mutagenesis with the subsequent development of hepatocellular carcinomas (HCCs) has been recurrently noted in newborn mice treated with high doses of AAV, and more recently, the association of wild-type AAV integrations in a subset of human HCCs has been documented. Here, we address, in a comprehensive, prospective study, the long-term risk of tumorigenicity in young adult mice following delivery of single-stranded AAVs targeting liver. HCC incidence in mice treated with therapeutic and reporter AAVs was low, in contrast to what has been previously documented in mice treated as newborns with higher doses of AAV. Specifically, HCCs developed in 6 out 76 of AAV-treated mice, and a pathogenic integration of AAV was found in only one tumor. Also, no evidence of liver tumorigenesis was found in juvenile AAV-treated mucopolysaccharidosis type VI (MPS VI) cats followed as long as 8 years after vector administration. Together, our results support the low risk of tumorigenesis associated with AAV-mediated gene transfer targeting juvenile/young adult livers, although constant monitoring of subjects enrolled in AAV clinical trial is advisable.

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