Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy?

Over the past three decades, a dogma has emerged regarding the uniform safety and nonpathogenicity of adeno-associated virus (AAV), for three excellent reasons. First, natural AAV infections in humans are common and until recently had not been associated with disease. Second, the recombinant AAV (rAAV) genome remains predominantly episomal, greatly reducing the risk of insertional mutagenesis and genotoxicity that was observed in clinical trials using retroviral vectors. Third, numerous human clinical trials and preclinical gene delivery studies in both small- and large-animal models have revealed no recognized vector toxicity other than the development of humoral and cellular immunity to the rAAV capsid.