ArticleMolecular therapy. Methods & clinical development2020
Site-Directed Mutagenesis Improves the Transduction Efficiency of Capsid Library-Derived Recombinant AAV Vectors.
Article in Molecular therapy. Methods & clinical development, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03003533 (Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A), which is not on this map. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A
Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- rAAV8 encapsidated HMR-001/z enables high efficiency hepatic transduction and restores hemostasis in hemophilic mice.Gene therapy · 2026Article
- Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- rAAV capsid mutants eliminate leaky expression from DNA donor template for homologous recombination.Nucleic acids research · 2024Article
- Humanization and functional characterization of enhanced coagulation factor IX variants identified through ancestral sequence reconstruction.Journal of thrombosis and haemostasis : JTH · 2024Article
- AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy.Microorganisms · 2023Review
- Improved gene therapy for MFRP deficiency-mediated retinal degeneration by knocking down endogenous bicistronicMolecular therapy. Nucleic acids · 2023Article
- Characterization of a Bioengineered AAV3B Capsid Variant with Enhanced Hepatocyte Tropism and Immune Evasion.Human gene therapy · 2023Article
- Reactive oxygen species enhance rAAV transduction by promoting its escape from late endosomes.Virology journal · 2023Article
- Enhanced sensitivity of neutralizing antibody detection for different AAV serotypes using HeLa cells with overexpressed AAVR.Frontiers in pharmacology · 2023Article
- Identification of Novel Retinal Pericyte-Targeting rAAV Vectors Through Directed Evolution.Translational vision science & technology · 2022Article
- Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.Blood advances · 2022Article
- Astrocyte Reprogramming in Stroke: Opportunities and Challenges.Frontiers in aging neuroscience · 2022Review
- Low endotoxinMolecular therapy. Methods & clinical development · 2021Article
- Optimization of AAV vectors to target persistent viral reservoirs.Virology journal · 2021Review
- Engineering andMolecular therapy. Methods & clinical development · 2020Article
- Role of Essential Metal Ions in AAV Vector-Mediated Transduction.Molecular therapy. Methods & clinical development · 2020Article
- Recent Advances in Gene Therapy for Hemophilia.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisReview
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Recombinant adeno-associated virus (rAAV) vectors selected from capsid libraries present enormous advantages in high selectivity of tissue tropism and their potential use in human gene therapy applications. For example, rAAV-LK03, was used in a gene therapy trial for hemophilia A (ClinicalTrials.gov: NCT03003533). However, high doses in patients resulted in severe adverse events and subsequent loss of factor VIII (FVIII) expression. Thus, additional strategies are needed to enhance the transduction efficiency of capsid library-derived rAAV vectors such that improved clinical efficacy can be achieved at low vector doses. In this study, we characterized two commonly used library-derived rAAV vectors, rAAV-DJ and rAAV-LK03. It was concluded that rAAV-DJ shared similar transport pathways (e.g., cell surface binding, endocytosis-dependent internalization, and cytoplasmic trafficking) with rAAV serotype 2, while rAAV-LK03 and rAAV serotype 3 shared similar transport pathways. We then performed site-directed mutagenesis of surface-exposed tyrosine (Y), serine (S), aspartic acid (D), and tryptophan (W) residues on rAAV-DJ and rAAV-LK03 capsids. Our results demonstrated that rAAV-DJ-S269T and rAAV-LK03-Y705+731F variants had significantly enhanced transduction efficiency compared to wild-type counterparts. Our studies suggest that the strategy of site-directed mutagenesis should be applicable to other non-natural AAV variants for their optimal use in human gene therapy.
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Registered trials
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.