Medicinal Products Based on Adeno-Associated Viral Vectors: A Regulatory Perspective on the Potential Risk of Insertion-Mediated Tumorigenesis.

The first marketed gene therapy medicinal products based on adeno-associated virus (AAV-GTMP) show promise for the treatment of various diseases, including rare diseases with unmet medical needs. AAV is traditionally considered nonpathogenic to humans, is incapable of self-replication, and, after introduction into various cell types, remains primarily episomal. Several reports have examined the risks of AAV-GTMP, including the risks associated with unintended integration events of elements from the recombinant (r) AAV vector into the host genome. Such events can be one of the steps in the multistep process of tumor formation. To date, rAAV-gene therapy (GT) vectors have not been shown to induce tumors in humans or non-rodent species, and the potential for rAAV-mediated carcinogenicity in humans is still considered theoretical. Nevertheless, a critical review of publicly available scientific data on rAAV-related integration events and a contextualization of the numbers of AAV-GT vector DNA integrations with the absolute burdens of environmental, lifestyle and background tumorigenic genotoxicities is warranted. From a regulatory perspective, it is advisable to implement a long-term safety follow-up for patients who have undergone treatment with high doses of AAV-GT, in accordance with the risk-based approach that has been established for advanced therapy medicinal products.