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Gene therapy

Permanent correction without selection

Nature Reviews Drug Discovery volume 4, page 372 (2005)Cite this article

The approach takes advantage of two fundamental biological processes: DNA recognition and DNA repair. Targeted cleavage of DNA is achieved by zinc-finger proteins that have been designed to recognize unique chromosomal sites and are fused to the non-specific DNA cleavage domain of a restriction enzyme. A double-strand break that is induced by the resulting ZFNs can create specific alterations in the genome by stimulating homology-directed repair between the locus of interest and an extrachromosomal donor molecule.

The authors designed a large collection of selected zinc-finger modules that would improve ZFN specificity and efficiency. They created a donor plasmid that carries a wild-type GFP sequence, which was introduced into cells along with a mutated GFP-encoding gene. Action by the ZFNs restored GFP function in 10% of cells — a substantial increase in homologous recombination frequency over that obtained in other selection-free settings. But can we achieve permanent and precise modification of an endogenous gene?

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References

ORIGINAL RESEARCH PAPER

  1. Urnov, F. D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 3 April 2005 (10.1038/nature03556)

FURTHER READING

  1. Jamieson, A. C. et al. Drug discovery with engineered zinc-finger proteins. Nature Rev. Drug Discov. 2, 361–368 (2003)

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Authors and Affiliations

  1. Nature Reviews Genetics,

    Ekat Kritikou

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  1. Ekat Kritikou
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Kritikou, E. Permanent correction without selection. Nat Rev Drug Discov 4, 372 (2005). https://doi.org/10.1038/nrd1736

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