Evaluating the State of the Science for Adeno-associated Virus Integration: An Integrated Perspective

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2022 Jun 12

PMID 35690906

Authors

Denise E Sabatino

Frederic D Bushman

Randy J Chandler

Ronald G Crystal

Beverly L Davidson

Ricardo Dolmetsch

Kevin C Eggan

Guangping Gao

Irene Gil-Farina

Mark A Kay

Douglas M McCarty

Eugenio Montini

Adora Ndu

Jing Yuan

Affiliations

Soon will be listed here.

Abstract

On August 18, 2021, the American Society of Gene and Cell Therapy (ASGCT) hosted a virtual roundtable on adeno-associated virus (AAV) integration, featuring leading experts in preclinical and clinical AAV gene therapy, to further contextualize and understand this phenomenon. Recombinant AAV (rAAV) vectors are used to develop therapies for many conditions given their ability to transduce multiple cell types, resulting in long-term expression of transgenes. Although most rAAV DNA typically remains episomal, some rAAV DNA becomes integrated into genomic DNA at a low frequency, and rAAV insertional mutagenesis has been shown to lead to tumorigenesis in neonatal mice. Currently, the risk of rAAV-mediated oncogenesis in humans is theoretical because no confirmed genotoxic events have been reported to date. However, because insertional mutagenesis has been reported in a small number of murine studies, there is a need to characterize this genotoxicity to inform research, regulatory needs, and patient care. The purpose of this white paper is to review the evidence of rAAV-related host genome integration in animal models and possible risks of insertional mutagenesis in patients. In addition, technical considerations, regulatory guidance, and bioethics are discussed.

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