Targeted gene delivery to the brain is crucial for neuroscience research and treating brain diseases. While invasive injections are common, focused ultrasound blood-brain barrier opening (FUS-BBBO) offers a noninvasive, site-specific alternative. However, using natural AAV serotypes with FUS-BBBO has limitations in transduction efficiency and causes significant peripheral organ transduction. This study utilizes high-throughput in vivo selection to engineer novel AAV vectors optimized for local neuronal transduction at FUS-BBBO sites. The engineered vectors significantly enhance ultrasound-targeted gene delivery and neuronal tropism while minimizing peripheral transduction, resulting in a more than ten-fold improvement in targeting specificity in two mouse strains.

Hongyi R. Li, Manwal Harb, John E. Heath, James S. Trippett, Mikhail G. Shapiro, Jerzy O. Szablowski