Better Understanding of AAV Integration is Necessary to Inform Patient Care

Last August, I participated in ASGCT’s AAV Integration Roundtable, a day-long event in which my colleagues and I discussed the status of AAV integration research to develop recommendations for risk assessment. After the event, I joined a group of experts to write a a review—recently published in Molecular Therapy—that captures current knowledge of AAV integration and lays out the challenges of assessing risk in humans in gene therapy studies. 

While the AAV genome primarily remains in an episomal form, AAV can integrate into the target cell genome at low frequency. Importantly, to date, there are no cases of AAV-associated tumorigenesis in clinical studies. However, studies in mouse models and, more recently, in large animal models after long term follow up, have raised concerns around the potential for AAV integration to lead to tumorigenesis.   

In this article, we discuss the evidence for AAV vector genome integration in animal models and assess the risk of insertional mutagenesis in patients. We also aim to highlight what is currently known about the role that AAV dose, vector design, and underlying liver disease may play in contributing to the risk of genotoxicity. Looking forward, we provide recommendations from experts in the field on methods of assessing integration, use of animal models, and clinical assessment of risk. Importantly, we raise the point that efforts should be made to collectively aggregate and share data. In addition, the regulatory perspective on AAV integration is also considered, as this topic has been discussed at recent FDA meetings. 

While the risk of malignancy in humans remains theoretical at this point, it is important for the field to have an ongoing discussion about AAV integration. Even though AAV can integrate at low frequency, there is remarkably little known about the mechanisms of integration, factors that may influence tumorigenesis and, ultimately, what the real risk may be in patients treated with AAV gene therapy. Thus, improving our understanding of AAV integration and its potential consequences will be essential to further define the safety of profile of AAV gene therapy. 

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Children's Hospital of Philadelphia.

Dr. Sabatino is research associate professor of pediatrics at the Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.