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

Recombinant adeno-associated viral (AAV) vectors are frequently used to deliver DNA into cells and are currently the leading platform for therapeutic gene delivery in humans. Presently, there is a need for optimized AAV vectors with improved transduction efficiencies in target tissues. In these studies, an engineered albumin-binding consensus domain (ABDCon) peptide 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. In C57BL/6J mice, AAV9-ABDCon achieved significantly higher levels of liver transduction compared with AAV9 following intravenous administration. These findings show that incorporation of the ABDCon peptide into the capsid VP2 N-terminus may be a potential method to augment AAV-mediated liver-directed gene delivery.