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The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice
Open accessAbstract
Vectors based on adeno-associated virus (AAV) serotype 9 are candidates for in vivo gene delivery to many organs, but the receptor(s) mediating these tropisms have yet to be defined. We evaluated AAV9 uptake by glycans with terminal sialic acids (SAs), a common mode of cellular entry for viruses. We found, however, that AAV9 binding increased when terminal SA was enzymatically removed, suggesting that galactose, which is the most commonly observed penultimate monosaccharide to SA, may mediate AAV9 transduction. This was confirmed in mutant CHO Pro-5 cells deficient in the enzymes involved in glycoprotein biogenesis, as well as lectin interference studies. Binding of AAV9 to glycans with terminal galactose was demonstrated via glycan binding assays. Co-instillation of AAV9 vector with neuraminidase into mouse lung resulted in exposure of terminal galactose on the apical surface of conducting airway epithelial cells, as shown by lectin binding and increased transduction of these cells, demonstrating the possible utility of this vector in lung-directed gene transfer. Increasing the abundance of the receptor on target cells and improving vector efficacy may improve delivery of AAV vectors to their therapeutic targets.
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“Another validated vector with broad tropism is AAV9, binding to terminal galactose and showing efficient transduction in CNS, eye, cardiac and skeletal muscle, and liver [50–53].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [51]
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Metadata
- Authors
- Bell, C. L., Vandenberghe, L. H., Bell, P., Limberis, M. P., Gao, G.-P., Van Vliet, K., Agbandje-McKenna, M., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Wilson, James M.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-06-01
- Volume
- 121
- Issue
- 6
- Pages
- 2427-2435
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3104778
- OpenAlex
- W2166540858
- Cited by
- 190
- References
- 40
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 9 · 2023: 14 · 2022: 13 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 13 · 2017: 5 · 2016: 8 · 2015: 12 · 2014: 18 · 2013: 19 · 2012: 20
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIH T32, NIH-R01, GM62116, DK047757)
- National Heart, Lung, and Blood Institute (P01HL059412, P01HL059407)
- National Institute of General Medical Sciences (GM082946, GM 62116, U54GM062116, R01GM082946)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007748, P30DK047757)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- AAV9, sialic acid, galactose, glycan binding, neuraminidase, airway epithelial cells, in vivo gene delivery, lectin binding
- MeSH terms
- Dependovirus, Animals, Capsid, Cricetulus, Galactose, Genetic Vectors, Glycosylation, Cricetinae, Lung, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Neuraminidase, Polysaccharides, Protein Binding, Receptors, Virus, Transduction, Genetic, Genetic Therapy, CHO Cells, Drug Delivery Systems, Mice
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