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Originally published In Press as doi:10.1167/iovs.09-3575 on October 8, 2009
 (Investigative Ophthalmology and Visual Science. 2010;51:1028-1035.)
© 2010 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3575
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Assessment of the Integrin {alpha}5β1 Antagonist JSM6427 in Proliferative Vitreoretinopathy Using In Vitro Assays and a Rabbit Model of Retinal Detachment

Grit Zahn,1,2 Kristine Volk,3 Geoffrey P. Lewis,4 Dörte Vossmeyer,1 Roland Stragies,1 Jeffrey S. Heier,5 Paul E. Daniel, Jr,5 Anthony P. Adamis,2 Ethan A. Chapin,4 Steven K. Fisher,4,6 Frank G. Holz,3 Karin U. Löffler,3 and Jochen Knolle1,2

From 1Jerini AG, Berlin, Germany; 2Jerini Ophthalmic, New York, New York; the 3Department of Ophthalmology, University of Bonn, Bonn, Germany; the 4Neuroscience Research Institute and the 6Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California; and 5Ophthalmic Consultants, Boston, Massachusetts.

Corresponding author: Grit Zahn, Senior Director, Lead Discovery Biology, Invalidenstrasse 130, 10115 Berlin, Germany; grit.zahn{at}gmx.net.

Purpose. To explore the role of integrin {alpha}5β1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression {alpha}5β1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule {alpha}5β1 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}5β1 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.

Results. Activated ARPE-19 cells and PVR membranes expressed high levels of {alpha}5β1; 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.

Conclusions. JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of {alpha}5β1–fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.






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