Vitiligo topical treatment applying a potent, highly selective MC1R agonist

使用强效、高选择性 MC1R 激动剂进行白癜风局部治疗

• 批准号: 10759768
• 负责人: ZALFA ABDEL-MALEK
• 金额: $ 29.59万
• 依托单位: MC1R VENTURES LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759768
• 关键词: Address; Adhesions; Adverse effects; Affect; Age; Agonist; Alopecia Areata; Anguish; Anti-Inflammatory Agents; Antioxidants; Anxiety; Autoimmune Process; Autoimmune Responses; Binding; Biological Assay; Calcineurin inhibitor; Caregivers; Cell surface; Cellular Immunity; Cessation of life; Child; Clinical Trials; Complex; Consumption; Cosmetics; Coupled; Cutaneous; DNA Damage; DNA Repair; Dangerousness; Data; Depressed mood; Diffusion; Dimethyl Sulfoxide; Disease; Emotional Stress; Ethnic Origin; Fontana-Masson stain; Formulation; Functional disorder; General Population; Generations; Genetic; Goals; Hashimoto Disease; Hematoxylin and Eosin Staining Method; Histology; Homeostasis; Human; Human Engineering; Hypersensitivity skin testing; Immune response; Immunocompromised Host; Inflammation Mediators; International; Investigational New Drug Application; JAK1 gene; Lead; Legal patent; Length; Lesion; Melanocortin 1 Receptor; Melanogenesis; Methotrexate; Mus; Organ; Oxidation-Reduction; Pathology; Pathway interactions; Patients; Penetration; Phase; Physiological; Pigmentation physiologic function; Population; Proliferating; Proteins; Psyche structure; Psychological Stress; Quality of life; Reactive Oxygen Species; Reading; Recurrence; Reporting; Research; Safety; Skin; Skin Pigmentation; Skin Substitutes; Stigmatization; Stratum Basale; Tacrolimus; Temperature; Testing; Therapeutic; Time; Topical Corticosteroids; Topical application; Toxic effect; Treatment outcome; Ultraviolet B Radiation; Uncertainty; United States Food and Drug Administration; Vitiligo; Woman; alpha-Melanocyte stimulating hormone; analog; biological adaptation to stress; burden of illness; commercialization; corticosteroid inhibitor; efficacy evaluation; efficacy validation; expectation; immunomodulatory therapies; in vivo; inhibitor; liquid chromatography mass spectrometry; melanocyte; neoantigens; novel; phase 2 study; pre-clinical; psychologic; receptor; side effect; skin color; skin lesion; social stigma; success; suicide rate; therapy outcome; ultraviolet; young adult

PROJECT SUMMARY Vitiligo is the most common acquired hypopigmentary disorder that afflicts 0.5-2% of the world population, from all ethnicities and skin color. It is characterized by loss of melanocytes, which is often progressive, resulting in depigmented skin lesions. Vitiligo can be segmental (5-16% of all cases) or most commonly, non-segmental. It is a disease of young adults, as 25% of all non-segmental vitiligo patients develop the disease by age 10, and 50% develop it by age 30. Vitiligo is erroneously perceived to be merely cosmetically disfiguring and not life- threating. However, in addition to other pathologies, such as alopecia areata and Hashimoto’s thyroiditis, the disease carries with it a tremendous psychological burden and social stigma, and a high rate of suicide, particularly in patients with skin of color. Repigmentation of vitiligo skin is difficult, time-consuming, and unpredictable. Even after successful repigmentation, there is 40% chance of recurrence of loss of pigmentation, which adds to the patients’ anxiety and mental anguish. Multiple mechanisms have been proposed for melanocyte destruction in vitiligo, including autoimmune response, generation of inflammatory mediators, genetic factors, pro-oxidant state in skin, and intrinsic melanocyte abnormalities and detachment. The immune response can be either the primary cause of melanocyte destruction or can be secondarily activated by neo- antigens expressed on melanocytes. We hypothesize that persistent and more rapid repigmentation of vitiligo skin will be achieved by targeting the melanocortin 1 receptor (MC1R) expressed on human melanocytes by topical application of a superpotent and selective agonist. The PI has reported that activation of MC1R expressed on human melanocytes by the physiological agonist α-melanocyte stimulating hormone (α-MSH) promotes melanocyte proliferation, attachment, survival, normal redox state and melanogenesis. These findings led her to develop potent tetrapeptide analogs of α-MSH that mimic its function in human melanocytes. Her major goal is to develop one of these tetrapeptide analogs, LK 184, which is highly selective for MC1R and 10-fold more potent than α-MSH, in a topical formulation to treat depigmented vitiligo lesions. The Specific Aims are to develop LK 184 in an optimal topical formulation and provide preclinical ex vivo and in vivo evidence of its efficacy and safety in stimulating long lasting pigmentation. The efficacy of LK 184 is supported by her data, and by reported clinical trials showing that the full length α-MSH analog NDP- α-MSH enhances repigmentation of vitiligo skin, when combined with narrow band UVB. However, NDP- α-MSH is not selective to MC1R, has extracutaneous effects, and has to be administered systemically. The expectations are that use of the first in class agent, LK 184, in combination with other existing treatments will have a huge positive impact on the quality of life of vitiligo patients, and limit the use of potentially dangerous immunosuppressives. The proposed studies will satisfy many requirements for regulatory approval of commercialization of LK 184 for vitiligo treatment by MC1R Ventures LLC.

项目总结 白癜风是最常见的获得性色素减退疾病，世界上0.5%-2%的人口受到这种疾病的困扰。 所有种族和肤色。它的特点是黑素细胞的丧失，这通常是进行性的，导致 脱色的皮肤损伤。白癜风可以是节段性的(占所有病例的5%-16%)，也可以是最常见的非节段性白癜风。它 是一种年轻人的疾病，因为25%的非节段性白癜风患者在10岁之前会患上这种疾病，并且 50%的人在30岁之前会患上这种病。白癜风被错误地认为只是美观的毁容，而不是生活- 威胁。然而，除了斑秃和桥本甲状腺炎等其他疾病外， 疾病带来了巨大的心理负担和社会耻辱，自杀率很高， 尤其是肤色不同的患者。白癜风皮肤的重新色素沉着是困难、耗时和 变幻莫测。即使在成功地重新着色后，也有40%的机会复发， 这增加了患者的焦虑和精神痛苦。已经提出了多种机制来实现 白癜风的黑素细胞破坏，包括自身免疫反应，炎性介质的产生， 遗传因素，皮肤中的促氧化状态，以及固有的黑素细胞异常和脱落。免疫者 反应可以是破坏黑素细胞的主要原因，也可以是由neo-2激活的。 黑素细胞上表达的抗原。我们假设，持续和更快的色素沉着 白癜风皮肤将通过靶向人类表达的黑素皮质素1受体(MC1R)来实现 黑素细胞通过局部应用一种超强而选择性的激动剂。私家侦探报告说 生理激动剂α-黑素细胞刺激剂对人黑素细胞表达的MC1R的激活作用 激素(α-MSH)促进黑素细胞的增殖、附着、存活、正常氧化还原状态和 黑色素生成。这些发现促使她开发出有效的α-MSH四肽类似物来模拟其功能 在人类黑素细胞中。她的主要目标是开发这些四肽类似物之一，LK 184，它具有高度的 在治疗脱色素白癜风的局部配方中，对MC1R具有选择性，比α-MSH有效10倍 损伤。具体目标是以最佳局部配方开发LK 184，并提供临床前体外试验 以及体内证据表明，它在刺激持久色素沉着方面的有效性和安全性。LK 184的疗效是 她的数据和报道的临床试验表明，全长α-MSH类似物NdP-α-MSH 增强白癜风皮肤的再色素沉着，当与窄波段UVB联合使用时。然而，ndp-α-msh不是 对MC1R有选择性，具有皮外效应，必须全身给药。人们的期望是 将第一类药物LK 184与其他现有治疗方法结合使用将产生巨大的积极影响 影响白癜风患者的生活质量，并限制潜在危险的免疫抑制剂的使用。 拟议的研究将满足监管部门批准LK 184商业化的许多要求 MC1R Ventures LLC治疗白癜风