In vivo genome editing restores haemostasis in a mouse model of haemophilia

In vivo genome editing restores haemostasis in a mouse model of haemophilia 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 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Springer Journals

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Publisher
Springer Journals
Copyright
Copyright © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
ISSN
0028-0836
eISSN
1476-4687
DOI
10.1038/nature10177
Publisher site
See Article on Publisher Site

Abstract

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

Journal

NatureSpringer Journals

Published: Jun 26, 2011

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