Adeno-associated virus (AAV)-based gene therapy products: What are toxicity studies in non-human primates showing us?

A number of adeno-associated virus (AAV)-based gene therapy products have entered clinical development, with a few also reaching marketing approval. However, as our knowledge of them grows from nonclinical and clinical testing, it has become apparent that various actual and theoretical safety issues can arise from their use. This review of 19 Good Laboratory Practice (GLP)-compliant toxicity studies in non-human primates (NHPs) with AAV-based gene therapy products via a variety of different dose routes in the period 2017-2021 showed results ranging from no study findings different from controls, or findings considered to be non-adverse, to actual toxicity, with changes highlighting careful monitoring in the clinic. Similar findings were found from a review of a number of published toxicity studies in NHPs. It was confirmed that studies have a role in evaluating for dorsal root ganglion (DRG) and/or peripheral nerve toxicity, hepatotoxicity, adverse immunogenicity and, to a lesser degree, insertional mutagenesis as well as other potential unacceptable findings such as adverse inflammation for ocular therapy candidates. Overall, it was demonstrated that toxicity (and biodistribution) studies in NHPs are a vital part of the safety assessment of AAV-based gene therapy products prior to clinical entry.