Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions

In the last two decades, recombinant adeno-associated virus has emerged as the most popular gene therapy vector. Recently AAV gene therapy has been approved by the FDA for the treatment of two rare genetic disorders, namely the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). As is the case for the treatment of SMA, if the AAV vector must be administered systemically, very high vector doses are often required for therapeutic efficacy. But higher vector doses inevitably increase the risk of adverse events. The tragic death of three children in a clinical trial to treat X-linked myotubular myopathy with an AAV vector has thrown this limitation into sharp relief. Regardless of the precise cause(s) that led to the death of the two children, it is critical that we develop better AAV vectors to achieve therapeutic levels of expression with lower vector doses. To transduce successfully a target cell, AAV has to overcome both systemic as well as cellular roadblocks. In this review, we discuss some of the most prominent cellular roadblocks that AAV must get past to deliver successfully its therapeutic payload. We also highlight recent advancements in our knowledge of AAV biology that can potentially be harnessed to improve AAV vector performance and thereby make AAV gene therapy safer.

Automated summary

Recombinant adeno-associated virus has become the most popular gene therapy vector in the last two decades, with higher doses increasing the risk of adverse events. FDA has recently approved AAV gene therapy for two rare genetic disorders, highlighting the need for better vectors to achieve therapeutic levels with lower doses. The review discusses cellular roadblocks that AAV must overcome and recent advancements in AAV biology that can improve vector performance for safer gene therapy.