Lymphocyte antigen 6 complex, locus A (Ly6a) (Ly6a)

Lymphocyte antigen 6 complex, locus A (Ly6a), commonly known as Sca-1, is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein belonging to the Ly6/uPAR family. While traditionally recognized as a marker for hematopoietic stem cells in mice, it has been identified as the critical receptor for the engineered adeno-associated virus (AAV) variant AAV-PHP.eB. This capsid variant interacts with Ly6a on the luminal surface of brain microvascular endothelial cells to facilitate highly efficient receptor-mediated transcytosis across the blood-brain barrier (BBB), enabling widespread gene delivery to the central nervous system (CNS) following systemic administration. The interaction between AAV-PHP.eB and Ly6a is highly species- and strain-specific; it is present in C57BL/6J mice but absent in BALB/c mice and primates, including humans. This lack of conservation presents a significant challenge for the clinical translation of AAV-PHP.eB-based therapies for neurodegenerative diseases. Consequently, research is ongoing to identify human orthologs, such as LY6E, that might serve as functional equivalents for CNS-targeted delivery in humans. Despite these translational hurdles, Ly6a remains a foundational target for understanding and engineering next-generation viral vectors for non-invasive brain gene therapy.

Other names

Sca-1Stem cell antigen-1Ly-6A.2Ly-6E.1T-cell-activating proteinTAP

Receptor-mediated transcytosis across the blood-brain barrier