Nature Medicine
8, 1427 - 1432 (2002)
Published online: 4 November 2002; | doi:10.1038/nm1202-795
Induction of angiogenesis in a mouse model using engineered transcription factorsEdward J. Rebar1, 3, Yan Huang2, 3, Reed Hickey2, Anjali K. Nath2, David Meoli2, Sameer Nath2, Bingliang Chen1, Lei Xu1, Yuxin Liang1, Andrew C. Jamieson1, Lei Zhang1, S Kaye Spratt1, Casey C. Case1, Alan Wolffe1
& Frank J. Giordano21
Sangamo Biosciences, Richmond, California, USA
2
Dept. of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
3
These authors contributed equally to this work.
Correspondence should be addressed to Frank J. Giordano fjg9@email.med.yale.eduThe relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied1. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences2,
3,
4,
5,
6,
7,
8,
9,
10. It has been proposed that such designed ZFPs may eventually be useful in gene therapy6,
7,
10. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice variants2. Preliminary studies in tissue culture have validated the feasibility of this approach2,
3,
4. The studies reported here were intended to test whether engineered transcription factors are effective in a whole-organism model. ZFPs were designed to regulate the endogenous gene encoding vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis and acceleration of experimental wound healing. In addition, the neovasculature resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that produced by expression of murine Vegfa
164 cDNA. These data establish, for the first time, that specifically designed transcription factors can regulate an endogenous gene in vivo and evoke a potentially therapeutic biophysiologic effect.
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