Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo
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 AA...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116303377 |
| _version_ | 1818493783131553792 |
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| author | James C Geoghegan Nicholas W Keiser Anna Okulist Inês Martins Matthew S Wilson Beverly L Davidson |
| author_facet | James C Geoghegan Nicholas W Keiser Anna Okulist Inês Martins Matthew S Wilson Beverly L Davidson |
| author_sort | James C Geoghegan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T17:58:31Z |
| format | Article |
| id | doaj.art-846efba02dc7447ba58086fe56d4b4f2 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-10T17:58:31Z |
| publishDate | 2014-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-846efba02dc7447ba58086fe56d4b4f22022-12-22T01:38:52ZengElsevierMolecular Therapy: Nucleic Acids2162-25312014-01-013C10.1038/mtna.2014.50Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In VivoJames C Geoghegan0Nicholas W Keiser1Anna Okulist2Inês Martins3Matthew S Wilson4Beverly L Davidson5Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USADepartment of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USADepartment of Internal Medicine, University of Iowa, Iowa City, Iowa, USADepartment of Internal Medicine, University of Iowa, Iowa City, Iowa, USADepartment of Internal Medicine, University of Iowa, Iowa City, Iowa, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USARecently, 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.http://www.sciencedirect.com/science/article/pii/S2162253116303377AAVbrain vasculaturecapsid engineeringchondroitin sulfateendotheliumphage displayreceptor |
| spellingShingle | James C Geoghegan Nicholas W Keiser Anna Okulist Inês Martins Matthew S Wilson Beverly L Davidson Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo Molecular Therapy: Nucleic Acids AAV brain vasculature capsid engineering chondroitin sulfate endothelium phage display receptor |
| title | Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo |
| title_full | Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo |
| title_fullStr | Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo |
| title_full_unstemmed | Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo |
| title_short | Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo |
| title_sort | chondroitin sulfate is the primary receptor for a peptide modified aav that targets brain vascular endothelium in vivo |
| topic | AAV brain vasculature capsid engineering chondroitin sulfate endothelium phage display receptor |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116303377 |
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