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Mol Ther. 2019 May 8;27(5):912-921. doi: 10.1016/j.ymthe.2019.02.013. Epub 2019 Feb 20.

The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier.

Author information

1
Gene Therapy Program, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
2
Regenerative Medicine Program, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
3
Gene Therapy Program, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: wilsonjm@upenn.edu.

Abstract

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.

KEYWORDS:

AAV-PHP.B; AAV-PHP.eB; CNS; LY6A; blood-brain barrier; gene therapy

PMID:
30819613
PMCID:
PMC6520463
[Available on 2020-05-08]
DOI:
10.1016/j.ymthe.2019.02.013

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