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Andy Whitlock, Zhenhua Huang, Yanli Wang, Laura Belen, Claire Mazow Gelfman; Evaluation of a Novel PI3-kinase Inhibitor in a Murine Model of Allergic Conjunctivitis: Treatment of Chronic Inflammation in Ocular Surface Disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4886.
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© ARVO (1962-2015); The Authors (2016-present)
Inflammation is a key player in the development of ocular surface diseases including Dry Eye and Chronic Allergic Conjunctivitis. Pharmacological intervention with PI3-Kinase (PI3K) inhibitors has been shown to alleviate systemic inflammation and thus represents an attractive therapeutic target for ocular disease. The purpose of this study was to test the anti-inflammatory potential of a novel PI3K inhibitor, KBP-7306, in a model of ocular surface inflammation.
The anti-inflammatory effect of 0.06% KBP-7306 was examined in a chronic Short Ragweed (SRW) Allergic Conjunctivitis model. Female Balb/C mice were sensitized with a subcutaneous injection of SRW, and then challenged 18 days later with topical SRW to determine responsiveness to the allergen sensitization and topical opththalmic challenge. Following the challenge, sensitized mice were randomized into treatment groups (n=8) and given test compounds four times daily on days 19-20 and three times daily on days 21-24. SRW challenges were repeated twice daily on days 21-24 for a total of 8 challenges; their responses to allergen were evaluated after challenges 1, 4, 6 and 8. Cyclosporine 0.05% (Restasis®) was used as a clinical comparator and Prednisolone acetate 1.0% was used as a positive control. KBP-7306 vehicle was used as the negative control. Following challenges hyperemia was evaluated using a Micron III imaging system. The allergic response was graded on a 0-4 scale using a modification of Ora’s clinical grading scale. Significance was determined using a Two-way ANOVA analysis and Bonferroni post-test comparing all treatment groups to the vehicle group.
Challenged mice treated with vehicle maintained a high level of allergen-induced hyperemia throughout the study, but decreased by .5 points on the final day (day 24). 0.06% KBP-7306 significantly decreased hyperemia on days 22 and 23 (P < 0.01 and P < 0.05 respectively). Treatment with both Prednisolone and Restasis decreased hyperemia throughout the entire challenge period. This effect was significant for both Prednisolone and Restasis on day 22 (P < 0.001 and P < 0.05 respectively) and for Prednisolone on day 23 (P < 0.01).
The data from this study confirms that the PI3K inhibitor KBP-7306 is an efficacious anti-inflammatory drug in this model of ocular surface inflammation.
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