A reconstructed skin model for development of treatments for albinism

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学和具体的挑战主题，15- od (ORDR)-101“预防、早期发现和治疗罕见疾病的试点项目”。2型皮肤白化病（OCA2）是一种常染色体隐性遗传病，由OCA2基因突变引起。虽然OCA2是世界上最常见的白化病，但它是一种罕见的疾病（3.9万分之一）。OCA2的患病率在非洲裔美国少数民族（1 / 10,000 {Witkop, 1989 #263}）和美洲原住民后裔（1 / 1,550-2,000基于载波频率的患病率{Yi， 2003 #1520}，但在一些霍皮群体中达到1 / 200 {Woolf， 1969 #1966}）中明显较高。OCA2导致皮肤、头发和眼睛色素沉着降低，以及视神经束错误和视网膜发育不良导致的视觉缺陷。除了视力丧失外，患皮肤癌的风险大大增加以及与高度可见性疾病相关的大量社会心理负担也会导致发病率。色素沉着是由于黑色素细胞不能产生黑色素，而黑色素可以保护皮肤免受紫外线辐射（UV）引起的损伤，并降低患皮肤癌的风险。患有OCA2的人生活在阳光强烈的地区，比如亚利桑那州，那里的纳瓦霍人更常见OCA2，风险最大。我们的实验室一直在研究OCA2的病因。与资助计划的目标一致，我们现在的目标是开发一种治疗性外用药物，以逆转OCA2的皮肤色素沉着，提供更好的防晒和减少疾病的心理负担。目前没有这样的治疗方法，也没有正在进行的临床试验来解决OCA2的治疗问题。我们通过筛选逆转培养小鼠白化黑素细胞色素沉着的化合物，确定了潜在的药物。在这个试点项目中，我们建议开发一个重建的人体皮肤模型，该模型将在临床试验中对患者进行药物治疗之前提供对人体功效的洞察。虽然“命中”化合物诱导色素沉着的能力将在小鼠和人类黑素细胞中得到验证，但这些实验并没有解决皮肤渗透和角质形成细胞代谢的问题，这可能使化合物惰性或更糟，产生有毒的副产品。因此，在重建的皮肤模型中进行测试将允许排除在三维模型中不能促进色素沉着的药物，从而减少失败的动物试验的数量。在Aim 1中，将开发一个重建的皮肤模型，该模型将纳入来自小鼠或患有OCA2的人类个体的黑色素细胞。该模型将用于Aim 2，以测试在我们最近的化学文库筛选中确定的药物的功效，通过它们促进白化黑素细胞色素沉着的能力。这些研究将促进OCA2色素沉着降低的临床试验和最终治疗。对OCA2的治疗将通过减少心理耻辱、癌症风险以及未来的视力缺陷，使患有该疾病的人在经济上更具生产力。此外，治疗剂的开发是创造就业机会的重要途径。开发和测试将需要学术界和制药业熟练工人的时间和努力，生产适销对路的治疗方法也是如此。该模型的效用将不仅限于OCA2，还可以扩展到任何形式的白化病或黑素细胞相关疾病，从而成倍地增加拟议研究的财务影响。OCA2是一种罕见的疾病，导致皮肤色素沉着减少，由于这种疾病的高度可见性，对受影响的个体造成严重的心理困扰，并使个体极易患上阳光诱发的皮肤癌。在这项研究中，我们的目标是建立一个重建的皮肤模型，该模型可用于测试在培养中逆转OCA2黑色素细胞色素表型的化合物的功效。这种治疗剂将逆转皮肤色素沉着，降低患皮肤癌的风险，减轻患有这种尚未治愈的疾病的人的社会心理负担，所有这些都将对患有这种疾病的人产生积极的经济影响，同时为开发色素沉着障碍的治疗方法提供新的途径，这将在学术界和制药业创造就业机会。

DESCRIPTION (provided by applicant): This application addresses the broad challenge area (15) Translational Science and the specific challenge topic, 15-OD (ORDR)-101 "Pilot projects for prevention, early detection and treatment of rare diseases." Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder resulting from mutations in the OCA2 gene. While OCA2 is the most common form of albinism worldwide, it is a rare disorder (1in 39,000). Prevalence of OCA2 is notably higher among American minorities of African descent ( 1 in 10,000 {Witkop, 1989 #263}) and Native American descent (prevalence of 1 in 1,550-2,000 based on carrier frequency {Yi, 2003 #1520}, but reaching 1 in 200 among some Hopi groups {Woolf, 1969 #1966}). OCA2 results in hypopigmentation of the skin, hair and eyes as well as visual deficits resulting from misrouting of the optic tract and maldevelopment of the retina. In addition to loss of visual acuity, greatly increased risk of skin cancers and substantial psychosocial burdens associated with a highly visible condition also contribute to morbidity. Hypopigmentation results from the failure of melanocytes to produce melanin which protects the skin against ultraviolet radiation (UV) induced damage and reduces the risk of cutaneous cancers. Individuals with OCA2 living in areas that experience intense sunlight, such as Arizona where OCA2 is more common among the Navajo, are at greatest risk. Our laboratory has been investigating the etiology of OCA2. Consistent with the objectives of the funding program, we now aim to develop a therapeutic topical agent that will reverse cutaneous hypopigmentation in OCA2, provide improved sun protection and reduce the psychological burden of the disease. No such treatments exist currently and there are no ongoing clinical trials to address the treatment of OCA2. We have identified potential agents by screening for compounds that reverse the hypopigmentation of murine albino melanocytes in culture. In this pilot project we propose the development of a reconstructed human skin model that will provide insight into human efficacy prior to subjecting patients to an agent in clinical trials. While the ability of the "hit" compounds to induce pigmentation will be verified in mouse and human melanocytes, these experiments do not address the issue of skin penetration and metabolism by keratinocytes, which may render the compound inert or worse, produce a toxic by-product. Thus testing in a reconstructed skin model will allow for exclusion of agents that fail to promote pigmentation in a three dimensional model thereby reducing the amount of failed animal tests. In Aim 1, a reconstructed skin model will be developed that will incorporate melanocytes from either mice or human individuals with OCA2. The model will be used in Aim 2 to test the efficacy of agents identified in our recent chemical library screen by their ability to promote pigmentation in albino melanocytes. These studies will facilitate the path to clinical trials and eventual treatment of hypopigmentation in OCA2. Treatment of OCA2 will allow those who suffer from the disease to be more economically productive by decreasing the psychosocial stigma, the risk of cancers and, in the future, visual defects. Moreover, development of therapeutic agents is a significant avenue for job creation. Development and testing will require the time and effort of skilled workers in both academia and the pharmaceutical industry as will production of a marketable treatment. The utility of this model will not be limited to OCA2, but can be extended to any form of albinism or melanocyte-related disease, exponentially increasing the financial impact of the proposed research. OCA2 is a rare disorder that results hypopigmentation of the skin which causes severe psychological distress to affected individuals due to the highly visible nature of the disease and renders individuals highly susceptible to sun-induced skin cancers. In this study we aim to develop a reconstructed skin model that can be used to test the efficacy of compounds that reverse the pigment phenotype of OCA2 melanocytes in culture. Such a therapeutic agent will reverse cutaneous hypopigmentation, reduce skin cancer risk and lessen the psychosocial burden in individuals with this as yet untreatable disorder, all of which will have a positive economic impact on those who suffer from the disease while providing a new pipeline for the development of therapeutics for pigmentation disorders, which will lead to the creation of jobs in both academia and the pharmaceutical industry.