Edward T Wei
University of California, USA
Title: Design of a cooling TRPM8 agonist to treat ocular discomfort
Biography
Biography: Edward T Wei
Abstract
Ocular discomfort is common because the eye surface has a high density of sensory nerve endings. Current methods for rapid (<5 min) and prolonged (>2 hr) relief of symptoms such as irritation, dryness, asthenopia, pruritus, and pain are limited. Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment has not been much studied. TRPM8,
an ion channel target on nerve endings, is associated with sensations of cooling and cold and was chosen here as drug target for screening lead candidates. The agonists called 1-dialkylphosphorylalkanes (Dapa) were chosen as the best source of prototypes by contrast to e.g. icilin, p-menthane carboxamides, p-menthane esters. In the design of an ideal agent, the goals are to select the correct target, and to deliver the right molecule to the right place at the right time. Dense TRPM8 innervation was found on the mouse eyelid and cornea, but not on the conjunctiva. The eyelid receptors were selected as drug targets. Lead candidates potently and selectively activate TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception). A prototype Dapa called cryosim-3 (C3) was tested in subjects with mild forms of dry eye disease (BMC Ophthalmology 2107). C3 applied to upper eyelids (n=30) elicited cooling
sensations, lasting 46 min and increased tear secretion. C3, 2 mg/mL in water, or water in a single-unit dispenser was applied 4x times daily for 2 weeks (n=20 per group) and data analyzed before and at 1 and 2 weeks thereafter. In questionnaire surveys of ocular discomfort indices (VAS scale, OSDI, and CVS symptoms), the C3 treatment group clearly showed improvement of symptoms at one and two weeks and an increase of basal tear secretion. No signs of irritation or pain were reported. C3 is a promising candidate for relief of ocular discomfort.