Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2
Abstract
The human parvovirus adeno-associated virus type 2 (AAV2) has many features that make it attractive as a vector for gene therapy. However, the broad host range of AAV2 might represent a limitation for some applications in vivo, because recombinant AAV vector (rAAV)-mediated gene transfer would not be specific for the tissue of interest. This host range is determined by the binding of the AAV2 capsid to specific cellular receptors and/or co-receptors. The tropism of AAV2 might be changed by genetically introducing a ligand peptide into the viral capsid, thereby redirecting the binding of AAV2 to other cellular receptors. We generated six AAV2 capsid mutants by inserting a 14-amino-acid targeting peptide, L14, into six different putative loops of the AAV2 capsid protein identified by comparison with the known three-dimensional structure of canine parvovirus. All mutants were efficiently packaged. Three mutants expressed L14 on the capsid surface, and one efficiently infected wild-type AAV2-resistant cell lines that expressed the integrin receptor recognized by L14. The results demonstrate that the AAV2 capsid tolerates the insertion of a nonviral ligand sequence. This might open new perspectives for the design of targeted AAV2 vectors for human somatic gene therapy.
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Rational design takes in-depth biological knowledge of existing AAV serotypes to predict and refine virus function with increased capsid tropism, enhanced transduction efficiency, and reduced immune response.
“Rational design takes in-depth biological knowledge of existing AAV serotypes to predict and refine virus function with increased capsid tropism, enhanced transduction efficiency, and reduced immune response [55, 56].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [55]
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- Authors
- Girod, A., Ried, M., Wobus, C., Lahm, H., Leike, K., Kleinschmidt, J., Deléage, G., & Hallek, M.
- Affiliations
- LMU Klinikum (DE)
- German Cancer Research Center (DE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Hallek, Michael
- Venue
- Nature Medicine
- Published
- 1999-09
- Volume
- 5
- Issue
- 9
- Pages
- 1052-1056
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1598111769
- Cited by
- 405
- References
- 0
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 15 · 2021: 9 · 2020: 10 · 2019: 16 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 13 · 2014: 11 · 2013: 5 · 2012: 21
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- 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
- Health Sciences › Medicine › Infectious Diseases › Parvovirus B19 Infection Studies
- Keywords
- adeno-associated virus type 2, capsid engineering, targeting peptides, integrins, viral tropism, gene therapy vectors, capsid mutants
- MeSH terms
- Dependovirus, Amino Acid Sequence, Binding, Competitive, Capsid, Heparin, Humans, Laminin, Ligands, Models, Molecular, Molecular Sequence Data, Mutation, Oligopeptides, Receptors, Virus, Recombinant Fusion Proteins, Transduction, Genetic, Tumor Cells, Cultured, Integrins, Mutagenesis, Insertional, Virus Assembly
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