Hudák, A., Roach, M., Pusztai, D. et al. (5 more authors) (2023) Syndecan-4 mediates the cellular entry of adeno-associated virus 9. International Journal of Molecular Sciences, 24 (4). 3141. ISSN 1661-6596
Abstract
Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS.
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Copyright, Publisher and Additional Information: | © 2023 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | ||||||
Keywords: | AAV9; cellular entry; gene delivery; heparan sulfate proteoglycans; syndecans | ||||||
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Institution: | The University of Sheffield | ||||||
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) | ||||||
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Depositing User: | Symplectic Sheffield | ||||||
Date Deposited: | 15 Mar 2023 16:14 | ||||||
Last Modified: | 15 Mar 2023 16:14 | ||||||
Status: | Published | ||||||
Publisher: | MDPI AG | ||||||
Refereed: | Yes | ||||||
Identification Number: | https://doi.org/10.3390/ijms24043141 | ||||||
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