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

English version

Autoři: Qin Huang ^aff001; Ken Y. Chan ^aff001; Isabelle G. Tobey ^aff001; Yujia Alina Chan ^aff001; Tim Poterba ^aff001; Christine L. Boutros ^aff002; Alejandro B. Balazs ^aff002; Richard Daneman ^aff003; Jonathan M. Bloom ^aff001; Cotton Seed ^aff001; Benjamin E. Deverman ^aff001
Působiště autorů: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States of America ^aff001; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States of America ^aff002; Departments of Neurosciences and Pharmacology, University of California, San Diego, La Jolla, CA, United States of America ^aff003; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States of America ^aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225206

Souhrn

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

Klíčová slova:

Mammalian genomics – Central nervous system – Cell binding – Immunohistochemistry techniques – Endothelial cells – Cell binding assay – Galactose – Capsids

Zdroje

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

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