I.11AAV vectors and the host immune system: a complicated relationship

Abstract

Gene transfer with adeno-associated virus (AAV) vectors is one of the most promising treatment modalities for neuromuscular disorders. Exciting results from clinical trials for diseases like spinal muscular atrophy, Duchenne muscular dystrophy, and X-linked myotubularin myopathy demonstrated the potential of the AAV vector technology in delivering unprecedent results in patients. Like in other AAV gene transfer trials, however, concerns related to immune-mediated toxicities associated with delivery of large vector doses prompted the use of transient prophylactic immunomodulation in several trials. The first evidence that AAV vectors can be immunogenic in humans came from the early trials of liver gene transfer, in which, for the first time, pre-existing immunity to wild-type AAV was identified a potential limiting factor of the platform in terms of efficacy and, potentially, safety. From these initial findings, our understanding of the immunological implication of AAV gene transfer has evolved significantly. Today, it is clear that immune responses triggered by AAV vectors are be the result of a combination of factors, which include the vector itself in all its components, pre-exposure to wild-type AAV, and host-specific variables. As such, a deep understanding of the vector-host immune system interactions is key to the ability to successfully modulate immune responses in gene transfer, to enable safe and persistent transgene expression and to allow for vector re-dosing, in case needed. While it is well established that vector immunogenicity can be a challenge to successful gene transfer, it should be kept in mind that not all immune responses associated with gene transfer are necessarily detrimental. Induction of transgene tolerance is in fact a key factor that plays a crucial role in transgene engraftment and, therefore, in achieving safe and long-lasting efficacy of gene transfer.