ArticleHuman gene therapy methods2015
Site-Directed Mutagenesis of Surface-Exposed Lysine Residues Leads to Improved Transduction by AAV2, But Not AAV8, Vectors in Murine Hepatocytes In Vivo.
Article in Human gene therapy methods, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 33 citations in OpenAlex.
- Review
- The role of post-translational modifications in parvovirus life cycle.Frontiers in veterinary science · 2025Review
- Emerging trends in virus and virus-like particle gene therapy delivery to the brain.Molecular therapy. Nucleic acids · 2024Review
- Rationale and strategies for the development of safe and effective optimized AAV vectors for human gene therapy.Molecular therapy. Nucleic acids · 2023Review
- Chemical modification of AAV9 capsid with N-ethyl maleimide alters vector tissue tropism.Scientific reports · 2023Article
- Identification of Novel Retinal Pericyte-Targeting rAAV Vectors Through Directed Evolution.Translational vision science & technology · 2022Article
- Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism.Molecular therapy. Nucleic acids · 2022Article
- Strategies to improve safety profile of AAV vectors.Frontiers in molecular medicine · 2022Review
- The significance of triple-capsid-mutant AAV8 for treatment of Sanfilippo Syndrome Type B.Archives of stem cell and therapy · 2022Article
- Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions.Gene therapy · 2021Review
- Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies.Frontiers in cellular neuroscience · 2021Review
- Adeno-Associated Viruses (AAV) and Host Immunity - A Race Between the Hare and the Hedgehog.Frontiers in immunology · 2021Review
- Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors.Molecular therapy. Methods & clinical development · 2020Review
- SUMOylation Targets Adeno-associated Virus Capsids but Mainly Restricts Transduction by Cellular Mechanisms.Journal of virology · 2020Article
- An essential N-terminal serine-rich motif in the AAV VP1 and VP2 subunits that may play a role in viral transcription.Virology · 2020Article
- Chemical modification of the adeno-associated virus capsid to improve gene delivery.Chemical science · 2019Article
- Post-translational modifications in capsid proteins of recombinant adeno-associated virus (AAV) 1-rh10 serotypes.The FEBS journal · 2019Article
- Next Generation of Adeno-Associated Virus Vectors for Gene Therapy for Human Liver Diseases.Gastroenterology clinics of North America · 2019Review
- Capsid Modifications for Targeting and Improving the Efficacy of AAV Vectors.Molecular therapy. Methods & clinical development · 2019Review
- Adeno-associated Virus (AAV) versus Immune Response.Viruses · 2019Review
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Authors and funding
8 authors at 2 institutions in 1 country.
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Abstract
The ubiquitin-proteasome pathway plays a critical role in the intracellular trafficking of recombinant adeno-associated virus 2 (AAV2) vectors, which negatively impacts the transduction efficiency of these vectors. Because ubiquitination occurs on lysine (K) residues, we performed site-directed mutagenesis where we replaced each of 10 surface-exposed K residues (K258, K490, K507, K527, K532, K544, K549, K556, K665, and K706) with glutamic acid (E) because of similarity of size and lack of recognition by modifying enzymes. The transduction efficiency of K490E, K544E, K549E, and K556E scAAV2 vectors increased in HeLa cells in vitro up to 5-fold compared with wild-type (WT) AAV2 vectors, with the K556E mutant being the most efficient. Intravenous delivery of WT and K-mutant ssAAV2 vectors further corroborated these results in murine hepatocytes in vivo. Because AAV8 vectors transduce murine hepatocytes exceedingly well, and because some of the surface-exposed K residues are conserved between these serotypes, we generated and tested two single mutants (K547E and K569E), and one double-mutant (K547 + 569E) AAV8 vector. However, no significant increase in the transduction efficiency of any of these mutant AAV8 vectors was observed in murine hepatocytes in vivo. These studies suggest that although targeting the surface-exposed K residues is yet another strategy to improve the transduction efficiency of AAV vectors, phenotypic outcome is serotype specific.
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