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 白癜风是最常见获得的急性疾病，影响了世界人口的0.5-2％， 所有种族和肤色。它的特征是丧失黑素细胞，这通常是渐进的，导致 皮肤损伤。白癜风可以是分段的（所有情况的5-16％）或最常见的是非段落。它 是年轻人的疾病，因为所有非段性白癜风患者中有25％在10岁之前发展出该疾病，并且 50％到30岁时就会发展它。白癜风被错误地认为仅是化妆品毁容而不是生命的 威胁。然而，除其他病理外，例如脱发和桥本甲状腺炎， 疾病带有巨大的心理伯恩（Burnen）和社会污名，并且自杀率很高， 特别是在有色皮肤的患者中。假场皮肤的重新构度很困难，耗时，并且 不可预测。即使成功抑制后，色素沉着丧失的可能性也有40％的机会 这增加了患者的动画和精神痛苦。已经提出了多种机制 白癜风的黑素细胞破坏，包括自身免疫反应，炎症介质的产生， 遗传因素，皮肤中的促氧化态以及内在的黑素细胞异常和脱离。免疫 反应可能是造成黑素细胞破坏的主要原因，也可以是由新的 在黑素细胞上表达的抗原。我们假设对 白癜风皮肤将通过针对人类表达的黑色皮质素1受体（MC1R）来实现 通过局部应用超牙和选择性激动剂的黑色素细胞。 PI报告了 通过物理激动剂α-核细胞刺激在人类黑素细胞上表达的MC1R激活 马酮（α-MSH）促进黑素细胞的增殖，附着，生存，正常氧化还原状态和 黑色素生成。这些发现使她开发了模仿其功能的α-MSH的潜在静脉肽类似物 她的主要目标是开发其中一种静脉肽类似物LK 184，这是高度的 在局部公式中，选择性MC1R的选择性比α-MSH的潜力高10倍 病变。具体的目的是以最佳局部配方开发LK 184并提供临床前的体内 并在体内证据表明其在刺激持久色素沉着中的有效性和安全性。 LK 184的效率是 由她的数据支持，并报告了临床试验，表明全长α-MSH模拟NDP-α-MSH 当与狭窄的频带UVB结合使用时，增强了白癜风皮肤的抑制作用。但是，NDP-α-MSH不是 对MC1R的选择性，具有严重的效果，必须系统地给药。期望是 班级代理商LK 184与其他现有疗法的结合使用将具有巨大的积极 对白癜风患者生活质量的影响，并限制使用潜在危险的免疫抑制剂。 拟议的研究将满足法规批准LK 184商业化的许多要求 MC1R Ventures LLC的白癜风处理。