Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

• DOI: 10.1371/journal.pone.0225206
• Publication Date: 2019-11-14T18:36:53Z
• Authors: Qin Huang; Ken Y. Chan; Isabelle G. Tobey; Yujia Alina Chan; Tim Poterba; Christine L. Boutros; Alejandro B. Balazs; Richard Daneman; Jonathan M. Bloom; Cotton Seed; Benjamin E. Deverman
• Keywords: Transduction (biophysics); Tissue tropism; HEK 293 cells; Adeno-associated virus

The engineered AAV-PHP.B family of adeno-associated virus efficiently delivers genes throughout the mouse central nervous system. To guide their application across disease models, and to inspire development translational gene therapy vectors for targeting neurological diseases in humans, we sought elucidate host factors responsible CNS tropism vectors. Leveraging differences 13 strains, systematically determined a set genetic variants that segregate with permissivity phenotype, rapidly identified LY6A as an essential receptor Interfering by CRISPR/Cas9-mediated Ly6a disruption or blocking antibodies reduced transduction brain endothelial cells AAV-PHP.eB, while ectopic expression increased AAV-PHP.eB HEK293T CHO 30-fold more. Importantly, demonstrate this newly discovered mode AAV binding can occur independently other known receptors. These findings illuminate previously reported species- strain-specific characteristics inform ongoing efforts develop next-generation vehicles human therapy.