Development of a Novel CRAC Channel Therapeutic for the Treatment of Primary Hyperhidrosis

Vivreon生物科学有限责任公司 圣卡罗尔峡谷路4940号110 加州圣地亚哥，邮编92121 邮箱：milton@vivreonbiosciences.com NIAMS PA-21-259 项目摘要 汗水是正常的生理汗液反应，有助于在热应激期间进行体温调节。 多汗症是由于正常的汗液控制失调而导致的不受控制的过度排汗。 机械装置。这是一种令人不快和尴尬的情况，影响到近5%的美国人口和 导致各行各业的个人业绩和经济贡献大幅下降， 它在很大程度上导致了焦虑和抑郁等令人衰弱的心理健康问题。当前 治疗方法包括强大的止汗剂，以及局部胆碱能拮抗剂(Qbrexza)和肉毒杆菌毒素 阻断导致原发性多汗症(PHH)的神经通路。这些治疗都不是完全有效的 由于疗效不佳、不便、副作用、费用高等问题，也没有受到患者的欢迎。新的 需要解决方案来抵消PHH对社会和情感的影响。 PHH反应严格依赖于钙释放激活的钙通道(CRAC)的功能。 汗腺，以及启动PHH的所有信号立即参与CRAC途径，使细胞内升高 无论最初的刺激如何，汗腺内的钙离子水平都会持续一段时间。这会使钙离子升高 反过来驱动单价离子通量，产生渗透梯度，导致水释放到腺管中。 并将汗水转移到表面降温。因此，CRAC通道是控制的理想目标 多汗症。在这里，Vivreon生物科学公司提议评估一种有效的小分子候选分子 调节CRAC通道作为治疗PHH的候选药物。目标一号将确定任何基因毒性或 用Ames法、染色体畸变法和紫外线依赖细胞毒性法检测细胞的光毒性。目标2将 开发合适的外用制剂，并使用人体皮肤测量该制剂的外用渗透率 活组织检查。目标3将测量局部应用后的复合疗效，并与 目前批准的治疗方法是针对标准多汗症模型中引起的出汗反应。成功 该项目的完成将促使Vivreon寻求额外资金，通过 所需的开发步骤，最终提交IND申请并探索与 皮肤科产品公司。

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.