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.

项目摘要 白癜风是最常见的后天性色素减退性疾病，困扰着世界人口的0.5-2%， 所有种族和肤色其特征在于黑素细胞的损失，这通常是进行性的，导致 皮肤色素脱失白癜风可以是节段性的（占所有病例的5-16%）或最常见的非节段性。它 白癜风是一种年轻人的疾病，因为所有非节段性白癜风患者中有25%在10岁时患上这种疾病， 50%的人在30岁时发展。白癜风被错误地认为只是美容毁容，而不是生活- 威胁然而，除了其他病理，如斑秃和桥本甲状腺炎， 疾病带来巨大的心理负担和社会耻辱，自杀率高， 尤其是有色皮肤的患者。白癜风的治疗方法有哪些？ 不可预测即使在成功地重新色素沉着后，仍有40%的机会复发色素沉着丧失， 这增加了患者的焦虑和精神痛苦。已经提出了多种机制， 白癜风中的黑素细胞破坏，包括自身免疫反应，炎症介质的产生， 遗传因素、皮肤中的促氧化状态、以及内在黑素细胞异常和脱落。免疫 反应可以是黑素细胞破坏的主要原因，也可以是由neo- 黑素细胞上表达的抗原。我们推测，持续和更快的色素沉着， 白癜风皮肤将通过靶向表达在人表皮细胞上的黑皮质素1受体（MC 1 R）来实现。 通过局部应用超强效和选择性激动剂来抑制黑素细胞。PI报告称， 通过生理激动剂α-黑素细胞刺激激活人黑素细胞上表达的MC 1 R 激素（α-MSH）促进黑素细胞增殖、附着、存活、正常氧化还原状态， 黑素生成这些发现使她开发出有效的α-MSH四肽类似物，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，这是高度 对MC 1 R具有选择性，比α-MSH强10倍，用于治疗色素脱失型白癜风的局部制剂 病变具体目标是开发LK 184的最佳局部制剂，并提供临床前离体给药。 以及其在刺激持久色素沉着中的有效性和安全性的体内证据。LK 184的功效是 她的数据支持，并报告了临床试验，表明全长α-MSH类似物NDP- α-MSH 当与窄波段UVB结合时，可增强白癜风皮肤的色素沉着。然而，NDP- α-MSH不是 对MC 1 R具有选择性，具有皮外作用，并且必须全身给药。期望值 第一种同类药物LK 184与其他现有治疗方法结合使用将产生巨大的积极作用。 影响白癜风患者的生活质量，并限制使用具有潜在危险的免疫抑制剂。 拟议的研究将满足LK 184商业化的监管批准的许多要求， 白癜风治疗由MC 1 R风险投资有限责任公司。