Adeno-Associated Virus Gene Therapy: Is There a Risk of Insertional Mutagenesis?

Adeno-associated virus (AAV) gene therapy has received approvals for the treatment of a number of rare monogenic disorders. There are questions surrounding the natural history of recombinant AAV (rAAV) vectors, which could provide insights into durability and long-term safety. Wild-type AAV (wtAAV) persists in extrachromosomal episomes and is also able to actively or passively integrate into the host genome. Although clonal wtAAV integration has been described in a small number of hepatocellular carcinoma cases, this at most represents a minor risk factor. Differences in the structure of wtAAV and rAAV limit translation of these studies. Recombinant AAV also persists in episomal forms with a small proportion becoming integrated. Some early murine studies demonstrated insertional mutagenesis after treatment with rAAV. These findings have not consistently been seen and are likely context-dependent (high-dose or neonatal treatment). There have been no reports of rAAV insertional mutagenesis in large animal models or human biopsy samples.