Focused ultrasound expands intra-CSF AAV delivery to deep brain regions in rats and non-human primates

A single administration of recombinant adeno-associated viruses (AAVs) has the ability to provide long-term gene expression in the brain, offering promising therapeutic options for neurodegenerative diseases that require decades of intervention. Intra-cerebrospinal fluid (CSF) administration is clinically relevant, and it enables broad transduction of superficial brain areas at lower doses compared with systemic delivery. However, intra-CSF AAV administration remains ineffective at transducing subcortical structures such as the striatum. We demonstrate in rats that following intra-CSF delivery of AAVs, targeting the striatum with focused ultrasound in the presence of intravenous microbubbles significantly enhances transduction in this brain region. When scaled to non-human primates, the AAV delivery to the caudate and putamen was increased up to 100-fold, and transgene expression up to 500-fold. These findings support intra-CSF administration of AAV combined with focused ultrasound as a promising strategy to extend gene delivery from superficial to deep brain structures with anatomical precision and clinical scalability.