In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy.
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.
1CEntre de Recherches, Thérapeutiques en Ophtalmologie, EA n degrees 2502, Faculté de Médecine Necker, Paris, France.
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L
Le Gat
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Gogat
C
C
Bouquet
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M
Saint-Geniez
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Darland
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Van Den Berghe
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Marchant
A
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Provost
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Perricaudet
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Menasche
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Abitbol
D000260:Adenoviruses, Human / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D043169:Endostatins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000628:therapy*; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D012709:Serum Albumin; D014568:Urokinase-Type Plasminogen Activator