Improvement of Outcome Measures of Dry Eye by a Novel Integrin Antagonist in the Murine Desiccating Stress Model

Abstract

Citation: Krauss AH, Corrales RM, Pelegrino FSA, Tukler-Henriksson J, Pflugfelder SC, de Paiva CS. Improvement of outcome measures of dry eye by a novel integrin antagonist in the murine desiccating stress model. Invest Ophthalmol Vis Sci. 2015;56:5888-5895. DOI:10.1167/ iovs.15-17249 PURPOSE. We investigated the effects of GW559090, a novel, competitive, and high-affinity a4 integrin antagonist, in a murine model of dry eye. Through interaction with vascular cell adhesion molecule 1 (VCAM-1) and fibronectin a4b1 integrin is involved in leukocyte trafficking and activation.METHODS. Female C57BL/6 mice, aged 6 to 8 weeks, were subjected to desiccating stress (DS). Bilateral topical twice daily 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) and expression of inflammatory markers in ocular surface tissues by real time PCR. Dendritic cell activation was measured in draining cervical lymph nodes (CLN) by flow cytometry. Separate groups of mice received GW559090 subcutaneously to evaluate the effects of systemic administration on corneal staining and cells in CLN.RESULTS. Topical GW559090 significantly reduced corneal uptake of OGD compared to vehicle-treated disease controls in a dose-dependent manner (1, 3, 10, and 30 mg/mL) with 30 mg/mL showing the greatest reduction in OGD staining. When administered topically, corneal expression of IL-1a, matrix metalloproteinase (MMP)-9, chemokine ligand 9 (CXCL9), and TGF-b1 was reduced in GW559090-treated eyes. Topical treatment with GW559090 decreased dendritic cell activation in lymph nodes. The effects on corneal staining and cellular composition in CLN were not reproduced by systemic administration of GW559090, suggestive of a local role for integrin antagonism in the treatment of dry eye.CONCLUSION. The novel a4 integrin antagonist, GW559090, improved outcome measures of corneal staining and ocular surface inflammation in this murine model of dry eye. These results indicate the potential of this novel agent for the treatment of dry eye disease.Keywords: experimental dry eye; a4b1 integrin antagonist, inflammation D ry eye disease (DED) is one of the most common and discomforting eye disorders. It has been defined as a multifactorial ocular surface disease more prevalent in women and the elderly. Dry eye disease is associated with symptoms of discomfort, visual disturbance, tear film instability, and inflammation of the ocular surface leading to potential damage to the ocular surface tissues. 1 The proinflammatory milieu is characterized by increased levels of cytokines and chemokines in the tear film, cornea, and conjunctiva, and increased autoreactive Tcell infiltration of the conjunctival epithelium and sometimes lacrimal gland 2-4 ; reviewed by Stern et al. 5,6 Alteration of the tear film composition (mucins, lipids, proteins) and decreased volume lead to tear film abnormalities that contribute to the disease ...

Cluster Analysis of Dry Eye Disease Models Based on Immune Cell Parameters – New Insight Into Therapeutic Perspective

“…To find the treatment molecule used in the selected papers, we showed Figure 4 and Table 2 . As treatments related to the immune factors, we could see the use of anti-inflammatory drugs corticosteroids, doxycycline, TNF-α blocker HL036, and immunosuppressant MK2i ( 8 , 10 , 17 ). Other than the immune factors, the treatment paradigm includes osmoprotectants (betaine, L-carnitine, and erythritol), amino acid (cyclosporine A), integrin-α4 antagonist (dexamethasone), artificial tears (epigallocatechin gallate (EGCG), hyaluronic acid), plant antioxidant ( 10 , 17 , 26 , 32 , 51 , 53 ).…”

Small-Molecule Antagonist of VLA-4 (GW559090) Attenuated Neuro-Inflammation by Targeting Th17 Cell Trafficking across the Blood-Retinal Barrier in Experimental Autoimmune Uveitis

“…Eyedrops (5µL) containing α4β1 integrin antagonist GW559090 ((S)-3-(4-((4-carbamoylpiperidine-1carbonyl)oxy)phenyl)-2-((S)-4-methyl-2-(2-(otolyloxy)acetamido)pentanamido) propanoic acid, kindly provided by GSK) solubilized in phosphate buffered saline (PBS, pH = 7) were given twice daily in both eyes either prophylactically (from days 0 to 14 post EAU induction) or therapeutically (from days 10 to 18 post EAU induction). The concentrations of GW559090 were selected based on previously published data [22,23]. GW559090 was solubilized in PBS and used at a nal concentration of 3 mg/ml (GW 3 ), 10 mg/ml (GW 10 ) or 30 mg/ml (GW 30 ) and compared to vehicle treated controls (Veh) or 0.1% dexamethasone eye drops (Maxidex®, Alcon, UK; Dex) as treatment controls.…”

“…The side effects of systemic administered integrin inhibitors has been reported with long term use, for example, infection and progressive multifocal leukoencephalopathy in Natalizumab (humanized α4 antibody) treating multiple sclerosis patients [21]. Recently, a topical α4β1 (VLA-4, CD49d/CD29) integrin inhibitor (GW559090) was shown to be clinically e cacious in a mouse model of dry eye disease [22][23][24]. It has been reported to exert its clinical effect through its high a nity binding to the α4β1/VLA-4 integrin and speci c blockade of cell interaction to VCAM-1 [22].…”

“…Recently, a topical α4β1 (VLA-4, CD49d/CD29) integrin inhibitor (GW559090) was shown to be clinically e cacious in a mouse model of dry eye disease [22][23][24]. It has been reported to exert its clinical effect through its high a nity binding to the α4β1/VLA-4 integrin and speci c blockade of cell interaction to VCAM-1 [22]. In this study, we investigated the effect of topically applied GW559090 in EAU, and the potential cellular mechanisms involved.…”

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

“…[139] In a desiccating stress murine model, a reduction of ocular surface inflammation was observed. [140] Furthermore, the drug was assessed in a clinical trial of 588 masked, randomized subjects who either were given a placebo (control) or received topically administered Lifitegrast (5.0%) (Twice a day) for a period of 84 days. [141] The subjects were evaluated at days 14, 42, and 84, and the primary measurement of efficacy was to observe a mean change from baseline inferior corneal staining score (ICSS).…”