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

Gene Therapy volume 12, pages 320–329 (2005)Cite this article

Abstract

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⩽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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Acknowledgements

We thank Ruben Hernandez-Alcoceba for help in designing the adenovirus vectors; Michael Clarke for helpful discussions and for critical review of this manuscript; Victor Rivera for critical review of this manuscript; and John Westman and Chris Strayhorn for help with the histology. We also thank ARIAD Pharmaceuticals (www.ariad.com/regulationkits) for the dimerizing agent AP20187. This research was supported in part by Grant DE14601 from NIH, and grant from the American Dental Association Health Foundation (JEN); Grants CA70057 (GN) and CA77266 (DMS) from the NIH; and by Grant 2 P30 CA46592-14 from NIH to the University of Michigan Comprehensive Cancer Center.

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Authors and Affiliations

  1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA

    W Song, Q Sun, Z Dong & J E Nör

  2. Department of Immunology, Baylor College of Medicine, Houston, TX, USA

    D M Spencer

  3. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    G Núñez

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  1. W Song
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  2. Q Sun
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  6. J E Nör
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Song, W., Sun, Q., Dong, Z. et al. Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector. Gene Ther 12, 320–329 (2005). https://doi.org/10.1038/sj.gt.3302306

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