The GPI-linked protein LY6A drives AAV-PHP.B transport across the blood-brain barrier

Parts used

Key findings

• The blood-brain barrier phenotype of AAV-PHP.B in C57BL/6J mice depends on a specific haplotype of the Ly6a locus (Sca-1), which encodes a glycosylphosphatidylinositol (GPI)-anchored protein. Whole-exome sequencing-based genetics mapped the strain dependence to Ly6a, and biochemical and genetic studies link high blood-brain barrier transport to binding of AAV-PHP.B to LY6A (SCA-1).

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.