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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要白癜风是最常见的后天性色素减退性疾病，困扰着世界 0.5-2% 的人口，所有种族和肤色的人都患有这种疾病，其特征是黑素细胞的损失，通常是进行性的，导致。色素脱失的皮肤病变可以是节段性的（占所有病例的 5-16%），或者最常见的是非节段性的。是一种年轻人的疾病，所有非节段性白癜风患者中有 25% 在 10 岁时患上这种疾病，并且 50% 的人在 30 岁时患上白癜风。人们错误地认为白癜风只是影响美观，而不是影响生活。然而，除了斑秃和桥本甲状腺炎等其他病症外，疾病带来巨大的心理负担和社会耻辱以及高自杀率，尤其是对于有色皮肤的患者来说，白癜风皮肤的重新色素沉着是困难、耗时的。即使在成功进行色素沉着后，仍有 40% 的机会再次出现色素丧失，这增加了患者的焦虑和精神痛苦，已提出多种机制。白癜风中黑色素细胞的破坏，包括自身免疫反应、炎症介质的产生、遗传因素、皮肤的促氧化状态以及内在黑素细胞异常和脱落。反应可能是黑素细胞破坏的主要原因，也可能是由新细胞激活的继发性激活。我们勇敢地面对黑色素细胞上表达的抗原的持续和更快速的重新染色。白癜风皮肤将通过靶向人类表达的黑皮质素1受体（MC1R）来实现 PI 报道称，通过局部应用超强选择性激动剂来抑制黑素细胞。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 MC1R 激素（α-MSH）促进黑素细胞增殖、附着、存活、正常氧化还原状态和这些发现促使她开发出模仿其功能的有效的 α-MSH 四肽类似物。她的主要目标是开发其中一种四肽类似物 LK 184，它具有高度的活性。对 MC1R 具有选择性，其效力比 α-MSH 强 10 倍，用于治疗脱色性白癜风的局部制剂具体目标是开发最佳局部制剂的 LK 184 并提供临床前体外试验。 LK 184 刺激持久色素沉着的功效和安全性的体内证据是。她的数据和报告的临床试验表明，全长 α-MSH 类似物 NDP-α-MSH 与窄谱 UVB 结合使用时，可增强白癜风皮肤的色素沉着，但 NDP-α-MSH 则不然。对 MC1R 具有选择性，具有皮肤外作用，并且必须全身给药。使用一流的药剂 LK 184 与其他现有治疗方法相结合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 商业化监管部门批准的许多要求 MC1R Ventures LLC 的白癜风治疗。