Assessment of the Integrin alpha 5 beta 1 Antagonist JSM6427 in Proliferative Vitreoretinopathy Using In Vitro Assays and a Rabbit Model of Retinal Detachment

作者：Zahn Grit^*; Volk Kristine; Lewis Geoffrey P; Vossmeyer Doerte; Stragies Roland; Heier Jeffrey S; Daniel Paul E Jr; Adamis Anthony P; Chapin Ethan A; Fisher Steven K; Holz Frank G; Loeffler Karin U; Knolle Jochen

来源：Investigative Ophthalmology & Visual Science, 2010, 51(2): 1028-1035.

DOI：10.1167/iovs.09-3575

PURPOSE. To explore the role of integrin alpha 5 beta 1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression alpha 5 beta 1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule alpha 5 beta 1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model.
METHODS. Expression of alpha 5 beta 1 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; IC(50) 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.
RESULTS. Activated ARPE-19 cells and PVR membranes expressed high levels of alpha 5 beta 1; expression was low in control eyes. JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC(50), 7.1 +/- 2.5 mu M) and inhibition of migration (IC(50), 6.0 +/- 4.5 mu M). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (Muller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachment.
CONCLUSIONS. JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of alpha 5 beta 1-fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells. (Invest Ophthalmol Vis Sci. 2010;51:1028-1035) DOI:10.1167/iovs.09-3575

• 出版日期2010-2