The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier
Open accessAbstract
Efficient delivery of gene therapy vectors across the blood-brain barrier (BBB) is the holy grail of neurological disease therapies. A variant of the neurotropic vector adeno-associated virus (AAV) serotype 9, called AAV-PHP.B, was shown to very efficiently deliver transgenes across the BBB in C57BL/6J mice. Based on our recent observation that this phenotype is mouse strain dependent, we used whole-exome sequencing-based genetics to map this phenotype to a specific haplotype of lymphocyte antigen 6 complex, locus A (Ly6a) (stem cell antigen-1 [Sca-1]), which encodes a glycosylphosphatidylinositol (GPI)-anchored protein whose function had been thought to be limited to the biology of hematopoiesis. Additional biochemical and genetic studies definitively linked high BBB transport to the binding of AAV-PHP.B with LY6A (SCA-1). These studies identify, for the first time, a ligand for this GPI-anchored protein and suggest a role for it in BBB transport that could be hijacked by viruses in natural infections or by gene therapy vectors to treat neurological diseases.
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LY6A 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 [119]
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 [119]
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- Authors
- Hordeaux, J., Yuan, Y., Clark, P. M., Wang, Q., Martino, R. A., Sims, J. J., Bell, P., Raymond, A., Stanford, W. L., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- University of Ottawa (CA)
- Corresponding author
- Wilson, James M.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 27
- Issue
- 5
- Pages
- 912-921
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6520463
- OpenAlex
- W2916541448
- Cited by
- 217
- References
- 48
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 31 · 2023: 22 · 2022: 34 · 2021: 38 · 2020: 33 · 2019: 12
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- Center for Outcomes Research and Evaluation, Yale School of Medicine
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Sca-1, AAV9, blood-brain barrier transport, gene therapy vectors, GPI-anchored proteins, ligand binding, neurological disease therapy
- MeSH terms
- Exome Sequencing, Dependovirus, Animals, Antigens, Ly, Biological Transport, Blood-Brain Barrier, Brain, Genetic Vectors, Hematopoiesis, Humans, Membrane Proteins, Neurons, Genetic Therapy, Glycosylphosphatidylinositols, Gene Transfer Techniques, Mice
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