Developing AAV Vectors for More Efficient and Selective Gene Expression in Specific Cell Types of the Nervous System Following Systemic Delivery

Abstract

Recombinant adeno-associated viruses (rAAVs) are commonly used as gene delivery vehicles in biomedical research and have shown great potential for gene therapy. Systemic administration of AAVs can be used to achieve broad vector distribution. However, key challenges remain with systemic administration of AAVs as their lack of organ and/or cell-type specificity may cofound experiments and cause off-target effects. We and others have evolved AAVs to direct their tropism towards specific organs, such as the brain, after systemic delivery. We previously described CREATE, a Cre-based selection method, and used it to develop AAVs that efficiently transduce the central nervous system (CNS) in adult rodents, namely AAV-PHP.B (Deverman et al, Nat. Biotech., 2016), a further enhanced variant, AAV-PHP.eB (Chan et al., Nat. Neurosci., 2017), and AAV-PHP.S (Chan et al., Nat. Neurosci., 2017), a variant that can efficiently transduce the peripheral nervous system (PNS) and several visceral organs.