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In vivo genome editing restores haemostasis in a mouse model of haemophilia
Open accessAbstract
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.
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“the initial efficiency of repair using zinc finger nucleases was also low and was substantially improved by subsequent work to correct hemophilia in mice12.”
From Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype (2014) · cites this paper as [12]
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Metadata
- Authors
- Li, H., Haurigot, V., Doyon, Y., Li, T., Wong, S. Y., Bhagwat, A. S., Malani, N., Anguela, X. M., Sharma, R., Ivanciu, L., Murphy, S. L., Finn, J. D., Khazi, F. R., Zhou, S., Paschon, D. E., Rebar, E. J., Bushman, F. D., Gregory, P. D., Holmes, M. C., & High, K. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Sangamo BioSciences (United States) (US)
- University of Pennsylvania (US)
- Corresponding author
- Holmes, Michael C.
- High, Katherine A.
- ORCID
- Venue
- Nature
- Published
- 2011-06-26
- Volume
- 475
- Issue
- 7355
- Pages
- 217-221
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3152293
- OpenAlex
- W2038866304
- Cited by
- 548
- References
- 29
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 13 · 2022: 22 · 2021: 19 · 2020: 34 · 2019: 33 · 2018: 48 · 2017: 54 · 2016: 66 · 2015: 62 · 2014: 66 · 2013: 44 · 2012: 40
- FWCI
- 35.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (P01HL064190, T32HL007150)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- zinc finger nucleases, genome editing, hemophilia B, in vivo gene targeting, DNA double-strand breaks, homology-directed repair, gene replacement, liver regeneration, genetic disease treatment
- MeSH terms
- Animals, Base Sequence, Hemophilia B, Disease Models, Animal, DNA Repair, Endonucleases, Exons, Factor IX, Genetic Vectors, Hemostasis, Humans, Introns, Liver, Liver Regeneration, Mice, Inbred C57BL, Mutation, Phenotype, Genetic Therapy, Zinc Fingers, Genome, Sequence Homology, Gene Targeting, Cell Line, Tumor, Mice, DNA Breaks, Double-Stranded, HEK293 Cells
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