ArticleNature2015
Promoterless gene targeting without nucleases ameliorates haemophilia B in mice.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 176 papers.
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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.
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Who cites it
176 citing papers in PubMed, 261 citations in OpenAlex.
- First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study.Gene therapy · 2026Trial
- Rapamycin nanoparticles mitigate anti-AAV antibody formation in a mouse model of ornithine transcarbamylase deficiency.Molecular therapy. Advances · 2026Article
- Functional editing of the OTC locus by targeted integration with phenotype correction and restoration of endogenous expression patterns.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Transforming Hemophilia Management: Lessons from Gene Therapy Clinical Trials.Molecular biotechnology · 2026Review
- Advancements in CRISPR-basedFrontiers in genome editing · 2026Review
- Review
- Spatiotemporal liver dynamics shape hepatocellular heterogeneity and impact in vivo gene engineering.Journal of hepatology · 2025Article
- Efficient AAV8 delivery to the liver via isolated hepatic perfusion and analysis of hepatic lobule transduction patterns.Liver research (Beijing, China) · 2025Article
- CRISPR/Cas9-mediated promoterless gene targeting reduces lysosome storage in MPS VII mice.Science China. Life sciences · 2025Article
- 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
- The deLIVERed promises of gene therapy: Past, present, and future of liver-directed gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer.Communications medicine · 2025Article
- Mouse B cells engineered to express an anti-HPV antibody elicit anti-tumor T cell responses.Frontiers in immunology · 2025Article
- CRISPR and gene editing technologies for bleeding disorders.Therapeutic advances in hematology · 2025Review
- Engineered human B cells targeting tumor-associated antigens exhibit antigen presentation and antibody-mediated functions.Frontiers in immunology · 2025Article
- Precision and efficacy of RNA-guided DNA integration in high-expressing muscle loci.Molecular therapy. Nucleic acids · 2024Article
- Lipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing.Biomolecules · 2024Article
- AAV-mediated genome editing is influenced by the formation of R-loops.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- R-loops facilitate AAV-mediated nuclease-free gene targeting.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Article
116 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Site-specific gene addition can allow stable transgene expression for gene therapy. When possible, this is preferred over the use of promiscuously integrating vectors, which are sometimes associated with clonal expansion and oncogenesis. Site-specific endonucleases that can induce high rates of targeted genome editing are finding increasing applications in biological discovery and gene therapy. However, two safety concerns persist: endonuclease-associated adverse effects, both on-target and off-target; and oncogene activation caused by promoter integration, even without nucleases. Here we perform recombinant adeno-associated virus (rAAV)-mediated promoterless gene targeting without nucleases and demonstrate amelioration of the bleeding diathesis in haemophilia B mice. In particular, we target a promoterless human coagulation factor IX (F9) gene to the liver-expressed mouse albumin (Alb) locus. F9 is targeted, along with a preceding 2A-peptide coding sequence, to be integrated just upstream to the Alb stop codon. While F9 is fused to Alb at the DNA and RNA levels, two separate proteins are synthesized by way of ribosomal skipping. Thus, F9 expression is linked to robust hepatic albumin expression without disrupting it. We injected an AAV8-F9 vector into neonatal and adult mice and achieved on-target integration into ∼0.5% of the albumin alleles in hepatocytes. We established that F9 was produced only from on-target integration, and ribosomal skipping was highly efficient. Stable F9 plasma levels at 7-20% of normal were obtained, and treated F9-deficient mice had normal coagulation times. In conclusion, transgene integration as a 2A-fusion to a highly expressed endogenous gene may obviate the requirement for nucleases and/or vector-borne promoters. This method may allow for safe and efficacious gene targeting in both infants and adults by greatly diminishing off-target effects while still providing therapeutic levels of expression from integration.
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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.