An engineered serum albumin-binding AAV9 capsid achieves improved liver transduction after intravenous delivery in mice

ABSTRACTRecombinant adeno-associated viral (AAV) vectors are frequently used to deliver nucleic acids for in vivo applications and are currently the leading platform for therapeutic gene delivery in gene therapy clinical trials. Presently, there is a need for improved AAV vectors with optimized transduction efficiency in target tissues. In these studies, an engineered albumin-binding consensus domain (ABDCon) was incorporated into the AAV9 capsid via fusion to the N-terminus of the AAV9 VP2 capsid protein to generate a variant AAV9 capsid with albumin-binding properties. The variant capsid, called AAV9-ABDCon, formed viable genome-containing vector particles and exhibited binding to human serum albumin. The AAV9 capsid, on the other hand, was not found to bind to human serum albumin by the methods used in this study. Following intravenous administration, the modified AAV9-ABDCon vector was found to achieve higher levels of transduction in liver tissue compared to AAV9. These findings suggest that serum albumin-binding may be a potential method to augment AAV-mediated liver-directed gene delivery.