ArticleHuman gene therapy methods2013
Bioengineering of AAV2 capsid at specific serine, threonine, or lysine residues improves its transduction efficiency in vitro and in vivo.
Article in Human gene therapy methods, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 88 citations in OpenAlex.
- Review
- The amazing AAV capsids: Into the structure-verse.Molecular therapy. Methods & clinical development · 2025Review
- Heavy-chain immunoglobulin locus editing in rhesus macaque B cells to confer antibody production.Molecular therapy. Methods & clinical development · 2025Article
- Suppressing microtubule detyrosination augments adeno-associated virus 2 endosomal escape and gene delivery.Journal of cell science · 2025Article
- Development and implementation of an LC-MS-based multi-attribute method for adeno-associated virus.Molecular therapy. Methods & clinical development · 2025Article
- Adeno-associated viral vector targeted evolution for neurofibromatosis gene delivery.Trends in molecular medicine · 2025Review
- Artificial Intelligence-Based Approaches for AAV Vector Engineering.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- The role of post-translational modifications in parvovirus life cycle.Frontiers in veterinary science · 2025Review
- Imaging of adeno-associated viral capsids for purposes of gene editing using CEST NMR/MRI.Magnetic resonance in medicine · 2024Article
- Transduction and Genome Editing of the Heart with Adeno-Associated Viral Vectors Loaded onto Electrospun Polydioxanone Nonwoven Fabrics.Biomolecules · 2024Article
- Intravitreal injection of new adeno-associated viral vector: Enhancing retinoschisin 1 gene transduction in a mouse model of X-linked retinoschisis.Biochemistry and biophysics reports · 2024Article
- Rapid characterization of adeno-associated virus (AAV) capsid proteins using microchip ZipChip CE-MS.Analytical and bioanalytical chemistry · 2024Article
- Designing molecules: directing stem cell differentiation.Frontiers in bioengineering and biotechnology · 2024Review
- Development of a Rapid Adeno-Associated Virus (AAV) Identity Testing Platform through Comprehensive Intact Mass Analysis of Full-Length AAV Capsid Proteins.Journal of proteome research · 2023Article
- Rationale and strategies for the development of safe and effective optimized AAV vectors for human gene therapy.Molecular therapy. Nucleic acids · 2023Review
- Biophysical characterization of adeno-associated virus capsid through the viral transduction life cycle.Journal, genetic engineering & biotechnology · 2023Review
- AAV vectors: The Rubik's cube of human gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- AAV-ie-K558R mediated cochlear gene therapy and hair cell regeneration.Signal transduction and targeted therapy · 2022Article
- Structurally Mapping Antigenic Epitopes of Adeno-associated Virus 9: Development of Antibody Escape Variants.Journal of virology · 2022Article
- Ocular Inflammation and Treatment Emergent Adverse Events in Retinal Gene Therapy.International ophthalmology clinics · 2021Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We hypothesized that the AAV2 vector is targeted for destruction in the cytoplasm by the host cellular kinase/ubiquitination/proteasomal machinery and that modification of their targets on AAV2 capsid may improve its transduction efficiency. In vitro analysis with pharmacological inhibitors of cellular serine/threonine kinases (protein kinase A, protein kinase C, casein kinase II) showed an increase (20-90%) on AAV2-mediated gene expression. The three-dimensional structure of AAV2 capsid was then analyzed to predict the sites of ubiquitination and phosphorylation. Three phosphodegrons, which are the phosphorylation sites recognized as degradation signals by ubiquitin ligases, were identified. Mutation targets comprising eight serine (S) or seven threonine (T) or nine lysine (K) residues were selected in and around phosphodegrons on the basis of their solvent accessibility, overlap with the receptor binding regions, overlap with interaction interfaces of capsid proteins, and their evolutionary conservation across AAV serotypes. AAV2-EGFP vectors with the wild-type (WT) capsid or mutant capsids (15 S/T→alanine [A] or 9 K→arginine [R] single mutant or 2 double K→R mutants) were then evaluated in vitro. The transduction efficiencies of 11 S/T→A and 7 K→R vectors were significantly higher (~63-90%) than the AAV2-WT vectors (~30-40%). Further, hepatic gene transfer of these mutant vectors in vivo resulted in higher vector copy numbers (up to 4.9-fold) and transgene expression (up to 14-fold) than observed from the AAV2-WT vector. One of the mutant vectors, S489A, generated ~8-fold fewer antibodies that could be cross-neutralized by AAV2-WT. This study thus demonstrates the feasibility of the use of these novel AAV2 capsid mutant vectors in hepatic gene therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.