Assessment of the integrin alpha5beta1 antagonist JSM6427 in proliferative vitreoretinopathy using in vitro assays and a rabbit model of retinal detachment.

Abstract

PURPOSE:

To explore the role of integrin alpha5beta1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression alpha5beta1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule alpha5beta1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model.

METHODS:

Expression of alpha5beta1 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 alpha5beta1; 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 microM) and inhibition of migration (IC(50), 6.0 +/- 4.5 microM). 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 alpha5beta1-fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.

• Authors: Grit Zahn, Kristine Volk, Geoffrey P Lewis, Dörte Vossmeyer, Roland Stragies, Jeffrey S Heier, Paul E Daniel Jr, Anthony P Adamis, Ethan A Chapin, Steven K Fisher, Frank G Holz, Karin U Löffler, Jochen Knolle
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 51 Issue 2 Pg. 1028-35 (Feb 2010) ISSN: 1552-5783 [Electronic] United States
• PMID: 19815730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibronectins
• Integrin alpha5beta1
• JSM6427
• Propionates
• Pyridines
• Pyrrolidines

Topics

• Animals
• Cell Adhesion (drug effects)
• Cell Line
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Epiretinal Membrane (metabolism)
• Female
• Fibronectins (metabolism)
• Flow Cytometry
• Humans
• Immunohistochemistry
• Integrin alpha5beta1 (antagonists & inhibitors, metabolism)
• Male
• Propionates (pharmacology)
• Pyridines (pharmacology)
• Pyrrolidines (pharmacology)
• Rabbits
• Retinal Detachment (metabolism, pathology, prevention & control)
• Retinal Pigment Epithelium (drug effects, metabolism)
• Vitreoretinopathy, Proliferative (etiology, metabolism, prevention & control)