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William Thelin, M. Ross Johnson, John Ansede, Karl Donn, Dongfang Yu, Barbara Grubb, Driss Zoukhri, Richard Boucher, Jose Boyer; Novel Topical Inhibitors of the Epithelial Sodium Channel (ENaC) Promote Sustained Increases in Tear Volume. Invest. Ophthalmol. Vis. Sci. 2013;54(15):958.
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Through the regulation of electrolyte and water transport, the ocular surface epithelium plays a critical role in the maintenance of tear volume and composition. As ENaC serves as the rate-limiting step for apical sodium transport and osmotic water absorption, we hypothesized that the inhibition of ENaC on ocular tissues would increase tear volume, thereby providing a novel therapeutic approach for treating the underlying cause of dry eye. Therefore we sought to (1) confirm the expression and activity of ENaC on the ocular surface; (2) explore the relationship between duration of ENaC inhibition and changes in tear volume; and (3) evaluate the impact of ENaC inhibition on ocular health in animal models of dry eye disease.
The expression of ENaC in ocular epithelia was measured in primary culture models, ex vivo tissue explants, and in vivo by molecular and functional bioelectric assays. The effect of a chemically diverse series of Parion ENaC blockers on tear volume was assessed in normal mice and a dry eye rat model (lacrimal excised + scopolamine rat or “ExLac”) by phenol red thread wicking. Finally, the effects of ENaC inhibition on improvements in dry eye signs and ocular health were tested in inflammatory-mediated (IL-1 mouse) and aqueous deficient (ExLac rats) animal models of dry eye.
We confirmed that ENaC subunits are broadly expressed and functional in the ocular surface epithelia of rodents and man. When applied topically to normal mice or ExLac rats, Parion ENaC blockers produce dose-dependent increases in tear volume, with the duration of effect being a function of the rate of drug clearance from the tear film. Significantly, we identified a series of ENaC blockers that are preferentially retained on the ocular surface, which increased tear volume in ExLac rats to normal levels for >6 hours after a single dose. In the IL-1 mouse and ExLac rat models of dry eye disease, treatment with ENaC blockers significantly improved tear volume and corneal fluorescein staining.
Our studies demonstrate that ENaC inhibitors provide long-acting increases in tear volume and that restoring volume alone is sufficient to provide significant improvements in ocular surface health in models of dry eye disease. Our data provide a clear rationale for the development of ENaC blockers to treat the underlying ocular surface desiccation in dry eye disease.
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