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Grit Zahn, Kristine Volk, Geoffrey P. Lewis, Dörte Vossmeyer, Roland Stragies, Jeffrey S. Heier, Paul E. Daniel, Anthony P. Adamis, Ethan A. Chapin, Steven K. Fisher, Frank G. Holz, Karin U. Löffler, Jochen Knolle; Assessment of the Integrin α5β1 Antagonist JSM6427 in Proliferative Vitreoretinopathy Using In Vitro Assays and a Rabbit Model of Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2010;51(2):1028-1035. doi: 10.1167/iovs.09-3575.
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© ARVO (1962-2015); The Authors (2016-present)
To explore the role of integrin α5β1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression α5β1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule α5β1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model.
Expression of α5β1 was evaluated on activated ARPE-19 cells by flow cytometry and on PVR membranes by immunohistochemistry. ARPE-19 cells were used in fibronectin-dependent adhesion and migration assays with various concentrations of JSM6427; IC50 was calculated. In the rabbit model, eyes were intravitreally injected with vehicle or JSM6427 on day 0 or 1 after retinal detachment; BrdU was administered intravitreally on day 3, and retinal tissues were harvested on day 3 (4 hours later) or 7. Retinal scarring, cellular proliferation, and inflammatory responses were quantified, and retinal morphology was analyzed in retinal sections.
Activated ARPE-19 cells and PVR membranes expressed high levels of α5β1; expression was low in control eyes. JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC50, 7.1 ± 2.5 μM) and inhibition of migration (IC50, 6.0 ± 4.5 μM). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (Müller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachment.
JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of α5β1–fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.
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