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G. Zahn, R. Stragies, M. Wills, S. Birkner, J. Knolle; Evaluation of Small Molecule Integrin Inhibitor for Ocular Neovascularization in Laser Induced CNV Model in Monkey . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4169.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The fibronectin receptor α5ß1 integrin was shown to be essential for angiogenesis. In literature studies, α5ß1–specific antibody inhibited pathological neovascularization in eyes. We designed highly potent (picomolar) and selective α5ß1 small molecule inhibitors. These compounds were evaluated in a variety of in vitro and in vivo models. The most disease relevant model for AMD was the laser–induced injury model of choroidal neovascularization in cynomolgus monkeys. Methods: The compounds were characterized in vitro using cell adhesion, migration and apoptosis assays. For the laser–induced CNV model, a total of 6 primates were used, and choroidal neovascularization (CNV) was induced by laser treatment to the maculae in both eyes of all animals on Day 1. Intravitreal injections of the inhibitor (150µg/eye) or vehicle were administered on Day 1, 8, 15, and 22. Fluorescein angiography (FA) was performed on Day 7, 14, 21 and 28, to determine the extent of neovascularization as determined by the leakage of fluorescein through neovessels, the validated endpoint of CNV in this model. Additionally, ERGs were recorded on Day 6, 13, 20 and 27, to evaluate the safety of intravitreal injection of the compound. Results: Selective α5ß1 small molecule inhibitors showed clear inhibitory activity in cellular adhesion of α5ß1 expressing cells to fibronectin in low nanomolar range. Additionally compounds inhibit migration and induce apoptosis of activated endothelial cells. In the laser induced CNV model, in animals receiving vehicle, peak neovascularization was detected 14 days after laser treatment, followed by gradual or no regression. Intravitreal injection of the inhibitor resulted in inhibition of neovascularization. Ophthalmologic examinations showed that no adverse effects were observed related to the administration of the compound. Conclusions: Intravitreal injection of α5ß1 inhibitor prevents neovascularization as determined in a model of CNV in primate. α5ß1 small molecule inhibitors potentially provide a new approach for inhibition of AMD as well as other neovascular diseases in the eye.
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