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In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy

Gene Therapy volume 10, pages 2098–2103 (2003)Cite this article

Abstract

Diabetic retinopathy and retinopathy of prematurity are among the leading causes of vision impairment throughout the world. Both diseases are characterized by pathological angiogenesis, which severely impairs vision. Extracellular proteinases play important roles in endothelial cell migration during angiogenesis. Amino-terminal fragment (ATF) is an angiostatic molecule that targets the uPA/uPAR system and inhibits endothelial cell migration. The angiostatic effect of ATF has been demonstrated in models of cancer, but has never been assessed in pathological retinal neovascularization. Endostatin also has angiostatic effects on tumor growth and retinal neovascularization.

We used an adenoviral vector carrying the murine ATF (AdATFHSA) or endostatin gene coupled to human serum albumin (HSA) (AdEndoHSA) to increase the half-life of the therapeutic protein in the circulation. We induced retinopathy by exposing 7-day-old mice to high levels of oxygen. They were intravitreally injected with the vectors. Local injection of AdATFHSA or AdEndoHSA reduced retinal neovascularization by 78.1 and 79.2%, respectively. Thus, the adenovirus-mediated delivery of ATFHSA or EndoHSA reduces retinal neovascularization in a mouse model of hypoxia-induced neovascularization.

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Acknowledgements

This work was supported by Association Retina France. We particularly thank the Dean of the Faculté de Médecine Necker, Patrick Berche and Professor Philippe Even for generously helping our team. We thank the Ministère de L'Enseignement Supérieur, de la Recherche et de la Technologie, INSERM, CNRS, Université Paris V, Association Française de lutte contre les Myopathies, Fondation pour la Recherche Médicale, Fondation de l'Avenir and Fondation de France. Laurence Le Gat is a recipient of PhD grants from L'Association pour la Recherche sur le Cancer and La Ligue Nationale Contre le Cancer. Karïn Gogat is a recipient of PhD grants from La ligue and La Société de Secours des Amis des Sciences. We warmly thank AVENTIS for allowing us to use their constructs for academic purposes.

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  1. L Le Gat, K Gogat, M Menasche and M Abitbol: These authors contributed equally to this work.

Authors and Affiliations

  1. CEntre de Recherches, Thérapeutiques en Ophtalmologie, EA n° 2502, Faculté de Médecine Necker, Paris, France

    L Le Gat, K Gogat, L Van Den Berghe, D Marchant, A Provost, M Menasche & M Abitbol

  2. UMR 8121, Vectorologie et Transfert de gènes, Institut Gustave Roussy, Villejuif, France

    C Bouquet & M Perricaudet

  3. Schepens Eye Institute, Harvard Medical School, Boston, MA, USA

    M Saint-Geniez & D Darland

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  1. L Le Gat
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  2. K Gogat
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  10. M Menasche
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Le Gat, L., Gogat, K., Bouquet, C. et al. In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy. Gene Ther 10, 2098–2103 (2003). https://doi.org/10.1038/sj.gt.3302122

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  • DOI: https://doi.org/10.1038/sj.gt.3302122

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