ArticleHuman gene therapy2012
AAV-mediated gene targeting is significantly enhanced by transient inhibition of nonhomologous end joining or the proteasome in vivo.
Article in Human gene therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- A Tripartite AAV System with Engineered Lox Sites Enables Efficient Delivery of theHuman gene therapy · 2026Article
- Enhancement of therapeutic transgene insertion for treatment of murine phenylketonuria.Molecular therapy. Nucleic acids · 2026Article
- Double-strand break repair pathways differentially affect processing and transduction by dual AAV vectors.Nature communications · 2025Article
- Article
- State-of-the-art 2023 on gene therapy for phenylketonuria.Journal of inherited metabolic disease · 2024Review
- Self-cleaving guide RNAs enable pharmacological selection of precise gene editing events in vivo.Nature communications · 2022Article
- Directed evolution of adeno-associated virus for efficient gene delivery to microglia.Nature methods · 2022Article
- Improved Genome Editing through Inhibition of FANCM and Members of the BTR Dissolvase Complex.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair in Tyrosinemia Type 1.Human gene therapy · 2021Article
- The role of small molecules in cell and gene therapy.RSC medicinal chemistry · 2021Review
- AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria.Molecular therapy. Methods & clinical development · 2020Article
- Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications.Cell biology and toxicology · 2020Review
- Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats.The Journal of biological chemistry · 2018Article
- Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model.EMBO molecular medicine · 2017Article
- Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens.Journal of virology · 2016Article
- A universal system to select gene-modified hepatocytes in vivo.Science translational medicine · 2016Article
- Genome Engineering Using Adeno-associated Virus: Basic and Clinical Research Applications.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Review
- Therapeutic genome editing: prospects and challenges.Nature medicine · 2015Review
- Article
- Variable correction of Artemis deficiency by I-Sce1-meganuclease-assisted homologous recombination in murine hematopoietic stem cells.Gene therapy · 2014Article
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Authors and funding
4 authors.
Funding
Abstract
Recombinant adeno-associated virus (rAAV) vectors have clear potential for use in gene targeting but low correction efficiencies remain the primary drawback. One approach to enhancing efficiency is a block of undesired repair pathways like nonhomologous end joining (NHEJ) to promote the use of homologous recombination. The natural product vanillin acts as a potent inhibitor of NHEJ by inhibiting DNA-dependent protein kinase (DNA-PK). Using a homology containing rAAV vector, we previously demonstrated in vivo gene repair frequencies of up to 0.1% in a model of liver disease hereditary tyrosinemia type I. To increase targeting frequencies, we administered vanillin in combination with rAAV. Gene targeting frequencies increased up to 10-fold over AAV alone, approaching 1%. Fah(-/-)Ku70(-/-) double knockout mice also had increased gene repair frequencies, genetically confirming the beneficial effects of blocking NHEJ. A second strategy, transient proteasomal inhibition, also increased gene-targeting frequencies but was not additive to NHEJ inhibition. This study establishes the benefit of transient NHEJ inhibition with vanillin, or proteasome blockage with bortezomib, for increasing hepatic gene targeting with rAAV. Functional metabolic correction of a clinically relevant disease model was demonstrated and provided evidence for the feasibility of gene targeting as a therapeutic strategy.
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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.