Cell-surface glycan receptors on blood-brain barrier endothelial and other transduced cells

Cell-surface glycan receptors on blood-brain barrier (BBB) endothelial and other transduced cells are the primary attachment factors for various viral vectors, most notably adeno-associated viruses (AAVs), used in gene therapy. These receptors consist of carbohydrate moieties such as heparan sulfate proteoglycans (HSPG), sialic acid, and galactose, which are ubiquitously expressed on the luminal surface of the BBB and the membranes of target central nervous system (CNS) cells like neurons and glia. Binding to these glycans represents the initial, low-affinity step in the viral infection process, serving to sequester and concentrate viral particles on the cell surface before they engage with high-affinity proteinaceous entry receptors like AAVR (KIAA0319L). In the context of CNS-directed therapies, the interaction between engineered AAV capsids and these glycan receptors is a key determinant of tissue tropism and the efficiency of BBB crossing via transcytosis. For example, AAV9 utilizes terminal galactose residues to achieve widespread CNS transduction, a property exploited by the FDA-approved therapy Zolgensma. Understanding the spatial distribution and density of these glycans is essential for optimizing the delivery of genetic payloads to the brain while minimizing off-target effects in peripheral organs.

Other names

Glycan attachment factorsAAV attachment receptorsHeparan sulfate proteoglycans (HSPG)Sialic acid receptorsGalactose receptorsCarbohydrate attachment factors

Capsid-glycan binding facilitates viral attachment and subsequent internalization or transcytosis across the blood-brain barrier.