Highly efficient endogenous human gene correction using designed zinc-finger nucleases View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-06

AUTHORS

Fyodor D. Urnov, Jeffrey C. Miller, Ya-Li Lee, Christian M. Beausejour, Jeremy M. Rock, Sheldon Augustus, Andrew C. Jamieson, Matthew H. Porteus, Philip D. Gregory, Michael C. Holmes

ABSTRACT

Permanent modification of the human genome in vivo is impractical owing to the low frequency of homologous recombination in human cells, a fact that hampers biomedical research and progress towards safe and effective gene therapy. Here we report a general solution using two fundamental biological processes: DNA recognition by C2H2 zinc-finger proteins and homology-directed repair of DNA double-strand breaks. Zinc-finger proteins engineered to recognize a unique chromosomal site can be fused to a nuclease domain, and a double-strand break induced by the resulting zinc-finger nuclease can create specific sequence alterations by stimulating homologous recombination between the chromosome and an extrachromosomal DNA donor. We show that zinc-finger nucleases designed against an X-linked severe combined immune deficiency (SCID) mutation in the IL2Rgamma gene yielded more than 18% gene-modified human cells without selection. Remarkably, about 7% of the cells acquired the desired genetic modification on both X chromosomes, with cell genotype accurately reflected at the messenger RNA and protein levels. We observe comparably high frequencies in human T cells, raising the possibility of strategies based on zinc-finger nucleases for the treatment of disease. More... »

PAGES

646

Journal

TITLE

Nature

ISSUE

7042

VOLUME

435

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature03556

    DOI

    http://dx.doi.org/10.1038/nature03556

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1040117781

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/15806097


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