title: Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo.
abstract: Recently, we described a peptide-modified AAV2 vector (AAV-GMN) containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Geoghegan
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Keiser
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Okulist
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Inês
authors.initials: I
authors.lastname: Martins
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Wilson
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA [2] Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson