Focused ultrasound-mediated AAV gene therapy: Unlocking a new space in the CNS delivery landscape

Adeno-associated viruses (AAVs) have emerged as the most clinically advanced platform for in vivo gene delivery, enabling durable therapeutic gene expression across a growing number of neurological disorders. However, successful delivery of AAVs to the brain requires navigating trade-offs among three interdependent factors: the vector dose administered, the resulting delivery efficacy within target cells, and the volume of brain tissue that can be effectively covered. While multiple clinical strategies have demonstrated that different positions within this delivery landscape can achieve therapeutic benefit, each approach carries important limitations, including surgical invasiveness, limited regional coverage, peripheral toxicity at high doses, manufacturing burden, or the risks associated with global brain transgene exposure. This review situates focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) within this broader CNS delivery landscape. Through the distinct mechanical mechanism of microbubble cavitation, FUS transiently and locally increases BBB permeability at user-defined targets, enabling systemically administered AAVs to enter the brain at high local concentrations while limiting transduction of non-targeted regions. We discuss how advances in large-volume sonication and FUS-optimized AAV capsids are converging to define an engineering path toward a clinically translatable delivery paradigm that is non-invasive, regionally selective, and highly efficient.

Abstract from PubMed (PMID 42995500). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.