Induction of angiogenesis in a mouse model using engineered transcription factors

  title={Induction of angiogenesis in a mouse model using engineered transcription factors},
  author={Edward J Rebar and Yan Huang and Reed P Hickey and Anjali K. Nath and David F. Meoli and Sameer Nath and Bingliang Chen and Lei Xu and Yuxin Liang and Andrew C. Jamieson and Lei Zhang and Sharon Kaye Spratt and Casey C. Case and Alan P. Wolffe and Frank J. Giordano},
  journal={Nature Medicine},
The relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences. It has been proposed that such designed ZFPs may eventually be useful in gene therapy. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice… 

Development of pro-angiogenic engineered transcription factors for the treatment of cardiovascular disease

  • E. Rebar
  • Biology
    Expert opinion on investigational drugs
  • 2004
Gene therapies that use engineered transcription factors to regulate a patient’s own endogenous genetic loci offer several advantages over cDNA-based approaches, including the capacity to upregulate

Gene Transfer of an Engineered Transcription Factor Promoting Expression of VEGF-A Protects Against Experimental Diabetic Neuropathy

VEGF-A–activating ZFP-TFs may ultimately be of clinical utility in the treatment of this disease and are suggested to be of significance for recapitulation of the proper biological responses stimulated by this potent neuroprotective growth factor.

Repression of vascular endothelial growth factor A in glioblastoma cells using engineered zinc finger transcription factors.

E engineered ZFP TFs are shown to be potent regulators of gene expression with therapeutic promise in the treatment of disease by creating potent transcriptional repressors that emulates the natural repression mechanism of these domains.

Transcription Factors Glioblastoma Cells Using Engineered Zinc Finger Repression of Vascular Endothelial Growth Factor A in Updated

E engineered ZFP TFs are shown to be potent regulators of gene expression with therapeutic promise in the treatment of disease by creating potent transcriptional repressors that emulate the natural repression mechanism of these domains.

Gene transfer of an engineered zinc finger protein enhances the anti-angiogenic defense system.

The data suggest that ZFP TF-driven enhancement of the endogenous anti-angiogenic defense system may provide a new approach for prophylaxis and treatment of neovascular diseases of the eye.

Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression

It is shown that Ad-p65 transfection of primary motor neurons results in VEGF variant expression and a significant increase in axon outgrowth in these cells, and adenoviral delivery of an engineered ZFP transcription factor inducing V EGF-A splice variant expression enhances nerve regeneration.

Regulation of the endogenous VEGF-A gene by exogenous designed regulatory proteins.

We describe a facile method to activate or repress transcription of endogenous genes in a quantitative and specific manner by treatment with designed regulatory proteins (DRPs), in which artificial

Regulation of endogenous gene expression using small molecule-controlled engineered zinc-finger protein transcription factors

This work has constructed a drug-responsive ZFP TF via the fusion of a ZFP DNA-binding domain (DBD) targeting the human VEGF-A gene and an effector domain containing a truncated progesterone receptor ligand- binding domain linked to the NFκB p65 activation domain.

An engineered VEGF‐activating zinc finger protein transcription factor improves blood flow and limb salvage in advanced‐age mice

  • Jun YuLi Lei F. Giordano
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2006
It is demonstrated that activation of the endogenous VEGFa gene by an engineered ZFP can induce angiogenesis in a clinically relevant model and the feasibility of designing ZFPs to therapeutically regulate gene expression in vivo is documented.

Muscular degeneration: Body building best without myostatin

  • M. Brazil
  • Biology
    Nature Reviews Drug Discovery
  • 2003
The first application of a designed zinc finger protein (ZFP) transcription factor in a whole organism is described — up-regulation of an endogenous gene encoding a protein that stimulates the growth of blood vessels.



Regulation of an Endogenous Locus Using a Panel of Designed Zinc Finger Proteins Targeted to Accessible Chromatin Regions

This work presents evidence for an enhanced activation of VEGF-A gene transcription by ZFP transcription factors fused to VP16 and p65 targeted to two distinct chromosomal sites >500 base pairs upstream or downstream of the transcription start site.

Synthetic Zinc Finger Transcription Factor Action at an Endogenous Chromosomal Site

Zinc finger transcription factors will provide a powerful tool to probe the determinants of chromatin accessibility and remodeling within endogenous chromosomal loci within human erythropoietin gene.

Isoforms of Vascular Endothelial Growth Factor Act in a Coordinate Fashion To Recruit and Expand Tumor Vasculature

It is found that only the intermediate isoform, VEGF164, could fully rescue tumor growth and the failure of the hypervascular V EGF188-expressing tumors to grow may be due to inadequate perfusion of the massive number of microvessels in these tumors.

Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular building blocks.

It is demonstrated that both gene repression and activation can be achieved by targeting designed proteins to a single site within the transcribed region of a gene, indicating that gene-specific transcriptional regulators of the type described here will find diverse applications in gene therapy, functional genomics, and the generation of transgenic organisms.

Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha.

Despite marked induction of hypervascularity, HIF-1alpha did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin.

Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor

The muscular vessels that developed from mother vessels in skin and perimuscle fat have the structure of collaterals and could be useful clinically in the relief of tissue ischemia and indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific.

In vitro selection of zinc fingers with altered DNA-binding specificity.

Random mutagenesis and phage display is used to alter the DNA-binding specificity of Zif268, a transcription factor that contains three zinc finger domains, with the greatest affinity being for the DNA binding site for which they were sorted.

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Design and selection of novel Cys2His2 zinc finger proteins.

Although there is no simple, general code for zinc finger-DNA recognition, selection strategies have been developed that allow these proteins to be targeted to almost any desired site on double-stranded DNA.