Many early-onset genetic diseases are rapidly progressive fatal conditions for which there has been limited or no therapeutic option. However, systemic gene therapy using adeno-associated viral (AAV) vectors has emerged as a viable therapeutic strategy owing to the long duration of effect of an AAV vector targeted to a terminally differentiated cell. The goal of systemic delivery is to reach body-wide cellular targets that are impacted by the underlying mutation and restore gene function. Sustained effects are more challenging in cell populations where cell growth is ongoing (such as in the musculature) since the AAV genomes remain episomal and are subject to dilution with nuclear division. In this paper, we consider the implications of systemic exposure to AAV vectors and the need for caution in implementation of these powerful tools to combat genetic disease using gene augmentation therapy and gene editing approaches that rely on AAV vector technology.

Improved understanding of the genetic basis and molecular pathogenesis for the majority of the severe and devastating inherited conditions is leading to very rapid progress in the development of AAV gene therapy for several previously untreatable conditions. Advances are also facilitated by the characterization of the different cellular tropisms of myriad naturally occurring or experimentally evolved AAV serotypes. By combining capsid tropism and promoter engineering with a deep understanding of the underlying biology of the disease being treated, first generation systemic AAV gene therapies have reached advanced stages of development or have received regulatory approval. 1