Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.

Publication Type	Review
Authors	Sabatino D, Bushman F, Chandler R, Crystal R, Davidson B, Dolmetsch R, Eggan K, Gao G, Gil-Farina I, Kay M, McCarty D, Montini E, Ndu A, Yuan J
Journal	Mol Ther
Volume	30
Issue	8
Pagination	2646-2663
Date Published	06/10/2022
ISSN	1525-0024
Keywords	Dependovirus, Genetic Vectors
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.
DOI	10.1016/j.ymthe.2022.06.004
PubMed ID	35690906
PubMed Central ID	PMC9372310