Gene Therapy Program, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
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.
Mol Ther. 2019 May 8;27(5):912-921. doi: 10.1016/j.ymthe.2019.02.013. Epub 2019 Feb 20.
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.
高效递送达血液-脑屏障（BBB）的基因治疗载体是神经疾病治疗的圣杯。一种称为 AAV-PHP.B 的神经亲和性载体腺相关病毒（AAV）血清型 9 的变体，已被证明在 C57BL/6J 小鼠中非常有效地将转基因递送到 BBB 中。基于我们最近观察到这种表型依赖于小鼠品系，我们使用基于全外显子组测序的遗传学将这种表型映射到淋巴细胞抗原 6 复合物、位置 A（Ly6a）（干细胞抗原-1 [Sca-1]）的特定单倍型上，该基因编码一种糖基磷脂酰肌醇（GPI）锚定蛋白，其功能一直被认为仅限于造血生物学。额外的生化和遗传研究明确将高 BBB 转运与 AAV-PHP.B 与 LY6A（SCA-1）的结合联系起来。这些研究首次确定了这种 GPI 锚定蛋白的配体，并表明它在 BBB 转运中的作用可能被天然感染中的病毒或基因治疗载体劫持，以治疗神经疾病。
