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Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood–retinal barrier

Gene Therapy volume 11, pages 865–873 (2004)Cite this article

Abstract

Several retinal and choroidal diseases are potentially treatable by intraocular delivery of genes whose products may counter or neutralize abnormal gene expression that occurs as part of the diseases. However, prior to considering a transgene, it is necessary to thoroughly investigate the effects of its expression in normal and diseased eyes. An efficient way to do this is to combine tissue-specific promoters with inducible promoter systems in transgenic mice. In this study, we used this approach to evaluate the effects of ectopic expression of angiopoietin-1 (Ang1) in normal eyes and those with ocular neovascularization. Adult mice with induced expression of Ang1 ubiquitously, or specifically in the retina, appeared normal and had no identifiable changes in retinal or choroidal blood vessels or in retinal function as assessed by electroretinography. Increased expression of Ang1 in eyes with severe retinal ischemia or in eyes with rupture of Bruch's membrane significantly suppressed the development of retinal or choroidal neovascularization, respectively. This inhibition of ocular neovascularization is particularly interesting and noteworthy, because overexpression of Ang1 in skin stimulates neovascularization. Ang1 also significantly reduced VEGF-induced retinal vascular permeability. These data suggest that intraocular delivery of ang1 has potential for treatment of ocular neovascularization and macular edema.

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Acknowledgements

This study was supported by EY05951, EY12609, and core Grant P30EY1765 from the NEI; Research to Prevent Blindness, Inc. (a Lew R Wasserman Merit Award (PAC)); Dr and Mrs William Lake.

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Author notes

  1. P A Campochiaro: DJZ is the Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology

  2. D J Zack: PAC is the George S and Dolores Dore Eccles Professor of Ophthalmology

Authors and Affiliations

  1. The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H Nambu, R Nambu, Y Oshima, S F Hackett, G Okoye, D J Zack & P A Campochiaro

  2. The Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H Nambu, R Nambu, Y Oshima, S F Hackett, G Okoye, D J Zack & P A Campochiaro

  3. Regeneron Pharmaceuticals, New York, USA

    S Wiegand & G Yancopoulos

  4. The Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Maumenee 719, Baltimore, MD, USA

    D J Zack

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  1. H Nambu
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Nambu, H., Nambu, R., Oshima, Y. et al. Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood–retinal barrier. Gene Ther 11, 865–873 (2004). https://doi.org/10.1038/sj.gt.3302230

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  • DOI: https://doi.org/10.1038/sj.gt.3302230

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