Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids.
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 s...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0225206 |
| _version_ | 1828746489826902016 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qin Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T04:25:32Z |
| format | Article |
| id | doaj.art-c8f3782bb38348a0822fd1454a18ee12 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-14T04:25:32Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c8f3782bb38348a0822fd1454a18ee122022-12-22T02:12:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-011411e022520610.1371/journal.pone.0225206Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids.Qin HuangKen Y ChanIsabelle G TobeyYujia Alina ChanTim PoterbaChristine L BoutrosAlejandro B BalazsRichard DanemanJonathan M BloomCotton SeedBenjamin E DevermanThe 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.https://doi.org/10.1371/journal.pone.0225206 |
| spellingShingle | 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 Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. PLoS ONE |
| title | Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. |
| title_full | Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. |
| title_fullStr | Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. |
| title_full_unstemmed | Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. |
| title_short | Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. |
| title_sort | delivering genes across the blood brain barrier ly6a a novel cellular receptor for aav php b capsids |
| url | https://doi.org/10.1371/journal.pone.0225206 |
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