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

By 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

Posted 01 Feb 2019
bioRxiv DOI: 10.1101/538421 (published DOI: 10.1371/journal.pone.0225206)

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 the development of translational gene therapy vectors useful for targeting neurological diseases in humans, we sought to elucidate the host factors responsible for the CNS tropism of AAV-PHP.B vectors. Leveraging CNS tropism differences across mouse strains, we conducted a genome-wide association study, and rapidly identified and verified LY6A as an essential receptor for the AAV-PHP.B vectors in brain endothelial cells. Importantly, this newly discovered mode of AAV binding and transduction is independent of other known AAV receptors and can be imported into different cell types to confer enhanced transduction by the AAV-PHP.B vectors.

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