Effects of a novel integrin antagonist, GW559090, in an experimental dry eye model

Abstract

Purpose: GW559090 is a novel, competitive and high-affinity α4β1 integrin antagonist. Through interaction with VCAM-1 and fibronectin α4β1 integrin is involved in leukocyte trafficking and activation. This study investigated the effects of GW559090 in a murine model of dry eye.

Methods: All studies were conducted according to the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals after review by the GSK Institutional Animal Care and Use Committee and in compliance with the ARVO Statement on the Use of Animals in Ophthalmic and Visual Research. Female C57BL/6 mice, aged 6 to 8 weeks, were subjected to desiccating stress (DS). Bilateral topical BID treatment with GW559090 was compared to vehicle treated controls. Treatment was initiated at the time of DS induction. Treatment effects were assessed on corneal staining with Oregon Green Dextran (OGD); conjunctival T cell infiltration by immunohistochemistry; expression of inflammatory markers in ocular surface tissues by real time PCR.

Results: Topical GW559090 significantly reduced corneal uptake of OGD compared to vehicle-treated disease controls in a dose dependent manner (1mg/ml; 3mg/ml; 10mg/ml; 30mg/ml) with 30mg/ml showing the greatest reduction in OGD staining (p<0.01). This effect was similar to inhibition of OGD staining achieved with topical dexamethasone. A significant decrease in the number of infiltrating CD4⁺ T cells in the conjunctival epithelium was observed in the GW559090-treated group compared to disease control (p<0.001). Conjunctival expression of IL-1α (p<0.001) and CCL20 (p<0.05) was reduced in GW559090 treated eyes.

Conclusions: GW559090, a novel α4β1 integrin antagonist, improved outcome measures of corneal staining, infiltrating CD4⁺ T cells and conjunctival IL-1α and CCL20 expression in this murine model of dry eye. These results indicate the potential of this novel agent for the treatment of dry eye disease.