Blood-brain barrier glycan receptors

Glycan receptors on the blood-brain barrier (BBB) and other transduced cells are carbohydrate-based cell surface molecules that serve as critical attachment sites for therapeutic delivery systems, most notably adeno-associated virus (AAV) vectors [2, 3]. These receptors include heparan sulfate proteoglycans (HSPG), sialic acids, and terminal galactose residues, which are differentially expressed across the brain microvasculature and parenchymal cells like neurons and glia [1, 2]. In the context of gene therapy, AAV capsids are engineered to bind these glycans to facilitate receptor-mediated endocytosis and subsequent transcytosis across the BBB, allowing the delivery of genetic payloads to the central nervous system [5, 6]. For example, AAV9 utilizes terminal galactose for CNS entry, while AAV2 relies on HSPG [2, 4]. Targeting these glycans is essential for treating neurological conditions such as spinal muscular atrophy and lysosomal storage diseases [5, 7]. However, the broad expression of these glycans in peripheral tissues, particularly the liver, presents a significant challenge for achieving CNS-specific transduction and avoiding systemic toxicity [5, 8].

Other names

BBB glycansHeparan sulfate proteoglycans (HSPG)Sialic acid receptorsGalactose receptorsEndothelial glycan receptorsCell surface glycoconjugates

Receptor-mediated transcytosis and viral entry via capsid-glycan interaction