Antiangiogenic gene therapy: Disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector

Baylor College of Medicine, Houston, Texas, United States
Gene Therapy (Impact Factor: 3.1). 03/2005; 12(4):320-9. DOI: 10.1038/
Source: PubMed


The activation of an inducible caspase (iCaspase-9) mediates apoptosis of neovascular endothelial cells, and overcomes the prosurvival effect of vascular endothelial growth factor or basic fibroblast growth factor. The potential utilization of direct activation of caspases as an antiangiogenic strategy for treatment of angiogenesis-dependent diseases (eg cancer) requires expression of the inducible caspase primarily in the tumor endothelium. The objective of this work was to develop and characterize a transcriptionally targeted adenoviral vector that mediates expression of iCaspase-9 specifically in neovascular endothelial cells. We observed that adenoviral vectors containing the human VEGFR2 promoter induced reporter gene expression primarily in proliferating human dermal microvascular endothelial cells (HDMEC). HDMEC transduced with recombinant adenoviral vectors containing iCaspase-9 under regulation of the VEGFR2 promoter (Ad-hVEGFR2-iCaspase-9) and exposed to a cell-permeable dimerizer drug (AP20187), presented higher caspase-3 activity and apoptosis than controls (P < or = 0.05). Using the SCID Mouse Model of Human Angiogenesis, we observed that local delivery of Ad-hVEGFR2-iCaspase-9 followed by intraperitoneal injection of AP20187 resulted in endothelial cell apoptosis and local ablation of microvessels. We believe that this constitutes the first report of a transcriptionally targeted antiangiogenic adenoviral vector that mediates neovascular disruption upon activation of a caspase-based artificial death switch.

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Available from: Jacques E Nör, Aug 07, 2014
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    • "Initial evaluation of the Robo4-driven Luc expression in endothelial cells in vitro demonstrated relatively low levels of promoter activity in comparison with AdH5CMVLuc. However, compared with other promoters tested to date (Cefai et al., 2005; Greenberger et al., 2004; Reynolds et al., 2001; Savontaus et al., 2002; Song et al., 2005; Takayama et al., 2007; Wung et al., 2005; Yang et al., 2006), the Robo4 promoter displayed significantly less liver tropism and higher endothelial-specific expression in vivo. Remarkably, the lung endothelial expression was specific and high, while the liver expression was barely detectable by immunohistochemistry analysis . "
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