VCAP-102 Achieves Exceptional BBB Penetration in Marmosets After Ten Years of AAV Capsid Evaluation

Abstract

Efficient passage of adenoassociated virus (AAV) vectors across the blood-brain barrier (BBB) is essential for achieving broad central nervous system transduction following systemic delivery. Since PHP.B was reported in 2016 to exhibit high BBB permeability in C57BL/6J mice, many BBB-penetrant capsids have been developed, yet their performance often varies substantially across species. From 2016 to 2025, we produced each newly reported BBB-penetrant capsid as its sequence became available and evaluated it under standardized intravenous administration conditions in marmosets. This included PHP.B, PHP.eB, AAV-F, CAP-B22, CAP-B10, CPP.16, CAP-Mac, and BR1N. Although several of these capsids have been reported to penetrate the marmoset BBB, none reproduced these effects under our unified evaluation conditions. We also pursued several directed-evolution approaches to engineer AAV9-based variants with improved BBB permeability; however, none surpassed AAV9. In 2025, VCAP-102 was reported as an AAV9-derived capsid with BBB permeability in mice and non-human primates. When evaluated using our standardized framework, VCAP-102 consistently mediated markedly stronger and more widespread whole-brain transduction than AAV9 across all three animals tested. These findings provide a decade-long, systematic assessment of BBB-penetrant AAV capsids in marmosets and identify VCAP-102 as a highly promising candidate for future systemically delivered AAV-based gene therapies.