Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids
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Abstract
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.
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LY6A is responsible for specific engagement to the 7-mer insertion of PHP.B and PHP.eB and for transcytosis at the BBB.
“Later, it was reported that lymphocyte antigen 6 complex, locus A (LY6A), a GPI-anchored membrane protein, responsible for specific engagement to the 7-mer insertion of PHP.B and PHP.eB and transcytosis at BBB [118, 119].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [118]
The Results section, “Interaction with Ly6a is necessary for the enhanced transduction phenotype of AAV-PHP.eB” (page unavailable), supports LY6A-dependent binding and transduction in mouse brain endothelial cells. The Discussion (page unavailable) reports increased binding by PHP.B variants with distinct seven-amino-acid insertions, but only suggests that LY6A could facilitate transcytosis across the C57BL/6J blood–brain barrier; it does not establish that transcytosis occurs through LY6A or that the insertion itself is the binding site. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLY6A homolog is highly and specifically present in brain endothelial cells of C57BL/6J mice but not in BALB/cJ mice and primates.
“However, LY6A homolog is highly and specifically presented in brain endothelial cells of C57BL/6 J mice but not in BALB/cJ mice and primates.”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [118]
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AAV-PHP.eB transduces both the inner and outer retina with high efficacy in mice
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- Authors
- Huang, Q., Chan, K. Y., Tobey, I. G., Chan, Y. A., Poterba, T., Boutros, C. L., Balazs, A. B., Daneman, R., Bloom, J. M., Seed, C., & Deverman, B. E.
- Affiliations
- Broad Institute (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of California San Diego (US)
- Corresponding author
- Deverman, Benjamin E.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-11-14
- Volume
- 14
- Issue
- 11
- Pages
- e0225206
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6855452
- OpenAlex
- W2986362275
- Cited by
- 234
- References
- 40
- Citations by year
- 2026: 28 · 2025: 33 · 2024: 39 · 2023: 30 · 2022: 34 · 2021: 38 · 2020: 28 · 2019: 4
- FWCI
- 15.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Stanley Center for Psychiatric Research, Broad Institute
- National Institute of Neurological Disorders and Stroke (UG3NS111689)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- blood-brain barrier, gene therapy vectors, receptor identification, mouse strain differences, brain endothelial cells, neurological disorders
- MeSH terms
- Dependovirus, Animals, Antigens, Ly, Blood-Brain Barrier, Brain, Cell Line, Genetic Vectors, Humans, Membrane Proteins, Neurons, Transduction, Genetic, Genetic Variation, Gene Transfer Techniques, Tropism, Transgenes, Mice
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