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

开发用于治疗原发性多汗症的新型 CRAC 通道疗法

• 批准号: 10546998
• 负责人: Milton L Greenberg
• 金额: $ 24.53万
• 依托单位: VIVREON BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546998
• 关键词: Affect; Anhidrosis; Animals; Anxiety; Attenuated; Automobile Driving; Autonomic Pathways; Axilla; Biological Assay; Biological Sciences; Biopsy; Botulinum Toxins; Chemicals; Cholinergic Antagonists; Chromosome abnormality; Chronic; Cream; Dermal; Dermatologic; Development; Dosage Forms; Dose; Drug Targeting; Duct (organ) structure; Eccrine Glands; Economics; Emotional; Formulation; Funding; Genetic; Gland; Goals; Grant; Heat Stress Disorders; Human; Hyperhidrosis disorder; Individual; Ions; Knock-out; Life; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Modeling; Movement; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Pathway interactions; Patient risk; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Phenotype; Phototoxicity; Physiologic Thermoregulation; Physiological; Population; Positioning Attribute; Prevention; Production; Productivity; Property; Reaction; Regimen; Rodent; Safety; Signal Transduction; Skin; Small Business Innovation Research Grant; Standard Model; Stimulus; Surface; Sweat Glands; Sweating; Synapses; Testing; Therapeutic; Topical application; Toxic effect; Toxicology; Walking; Water; animal efficacy; candidate validation; clinical candidate; clinical development; combat; cost; cytotoxicity; driving force; druggable target; efficacy study; first-in-human; genotoxicity; ineffective therapies; nerve supply; novel; patient population; programs; research clinical testing; response; side effect; small molecule; social; therapeutic candidate; therapeutically effective; treatment duration; water flow

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 [e-mail] 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.

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA [e-mail] NIAMS PA-21-259 项目摘要 出汗是在热应激期间有助于体温调节的正常生理汗液反应。 多汗症是由于正常汗液控制失调而产生的不受控制和过量的汗液 机制等这是一种令人不快和尴尬的状况，影响了近5%的美国人口， 导致各行各业的个人的业绩和经济贡献显著下降， 而且它对焦虑和抑郁等精神健康问题有很大的影响。电流 治疗方法包括强效止汗剂、局部胆碱能拮抗剂（QbrexzaTM）和BOTOXTM， 阻断驱动原发性多汗症（PHH）的神经支配途径。这些治疗方法既不完全有效， 由于诸如无效、不便、副作用和高成本等问题而不被患者接受。新 需要解决方案来抵消PHH的社会和情感影响。 PHH反应严格依赖于细胞内Ca 2+释放激活的Ca 2+（CRAC）通道的功能。 汗腺和所有启动PHH的信号立即参与CRAC通路，以提高细胞内 无论初始刺激如何，持续一段时间的外分泌汗腺中的Ca 2+水平。这使Ca 2 + 反过来驱动单价离子流，产生渗透梯度，导致水释放到腺管中 以及汗液向表面运动以冷却。因此，CRAC信道是用于控制 多汗症在这里，Vivreon Biosciences提议评估一种有效的小分子候选物 调节CRAC通道作为治疗PHH的治疗候选物。目标1将确定任何遗传毒性或 使用艾姆斯、染色体畸变和UV依赖性细胞毒性试验测定光毒性潜力。目标2将 开发合适的局部制剂并使用人皮肤测量制剂的局部渗透 活组织检查目的3将测量单独局部施用和与药学上可接受的赋形剂组合后的化合物功效。 目前批准的针对在多汗症标准模型中引起的出汗反应的治疗。成功 该项目的结束将促使Vivreon寻求额外的资金来推进PHH计划， 所需的开发步骤，最终在IND申请和探索合作机会， 皮肤科产品公司。