ArticleGenome biology2019
Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse.
Article in Genome biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 75 citations in OpenAlex.
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- Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes.Communications medicine · 2025Article
- Anionic polymer coating for enhanced delivery of Cas9 mRNA and sgRNA nanoplexes.Biomaterials science · 2025Article
- Enhancing hemophilia A gene therapy by strategic F8 deletions in AAV vectors.Blood science (Baltimore, Md.) · 2025Article
- CRISPR and gene editing technologies for bleeding disorders.Therapeutic advances in hematology · 2025Review
- Lipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing.Biomolecules · 2024Article
- OliTag-seq enhances in cellulo detection of CRISPR-Cas9 off-targets.Communications biology · 2024Article
- Targeted Gene Insertion: The Cutting Edge of CRISPR Drug Development with Hemophilia as a Highlight.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Decoding the complexity of on-target integration: characterizing DNA insertions at the CRISPR-Cas9 targeted locus using nanopore sequencing.BMC genomics · 2024Article
- Hemophilia Healing with AAV: Navigating the Frontier of Gene Therapy.Current gene therapy · 2024Review
- Article
- GREPore-seq: A Robust Workflow to Detect Changes After Gene Editing Through Long-range PCR and Nanopore Sequencing.Genomics, proteomics & bioinformatics · 2023Article
- Superior Fidelity and Distinct Editing Outcomes of SaCas9 Compared with SpCas9 in Genome Editing.Genomics, proteomics & bioinformatics · 2023Article
- Innovations in RNA therapy for hemophilia.Blood · 2023Review
- CRISPR-Cas9 assisted non-homologous end joining genome editing system of Halomonas bluephagenesis for large DNA fragment deletion.Microbial cell factories · 2023Article
- Bioinformatic and literature assessment of toxicity and allergenicity of a CRISPR-Cas9 engineered gene drive to control Anopheles gambiae the mosquito vector of human malaria.Malaria journal · 2023Article
- Review
- Correction ofFrontiers in genetics · 2023Article
Corrections and comments
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Authors and funding
22 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%).
resultsWe report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects.
conclusionsThese findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components.
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