Development of a Novel CRAC Channel Therapeutic for the Treatment of Primary Hyperhidrosis - Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAMS PA-21-259 Project Summary Hidrosis is the normal physiological sweat response that contributes to thermoregulation during heat stress. Hyperhidrosis is the uncontrolled and excessive production of sweat due to dysregulation of normal sweat control mechanisms. This is an unpleasant and embarrassing condition that affects nearly 5% of the US population and causes significant reduction in performance and economic contribution amongst individuals from all walks of life, and it contributes substantially to debilitating mental health issues like anxiety and depression. Current treatments include powerful anti-perspirants, and topical cholinergic antagonists (Qbrexza) and BOTOX that block innervation pathways that drive primary hyperhidrosis (PHH). These treatments are neither fully effective nor embraced by the patients due to issues such as inefficacy, inconvenience, side effects, and high cost. New solutions are needed to offset the social and emotional impact of PHH. The PHH response is strictly dependent on function of the Ca2+ release activated Ca2+ (CRAC) channels in the sweat gland, and all signals that initiate PHH immediately engage the CRAC pathway to elevate intracellular Ca2+ levels in the eccrine sweat gland for sustained periods regardless of the initial stimulus. This elevated Ca2+ in turn drives monovalent ion fluxes, creating the osmotic gradient that leads to water release into the gland duct and movement of sweat to the surface for cooling. As such, the CRAC channel is an ideal target for control of hyperhidrosis. Here, Vivreon Biosciences proposes to evaluate a small molecule candidate that potently modulates CRAC channels as a therapeutic candidate for treating PHH. Aim 1 will determine any genotoxic or phototoxic potential using the Ames, chromosomal aberration, and UV-dependent cytotoxicity assays. Aim 2 will develop a suitable topical formulation and measure the topical penetration of the formulation using human skin biopsies. Aim 3 will measure compound efficacy following topical application alone and in combination with a currently approved therapy against a sweating response elicited in a standard model of hyperhidrosis. Successful conclusion of this project will trigger Vivreon to seek additional funding to advance the PHH program through required development steps culminating in an IND filing and exploration of partnership opportunities with dermatological product companies.
