A reconstructed skin model for development of treatments for albinism

描述(由申请人提供)：本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“罕见疾病预防、早期发现和治疗的试点项目”。眼皮肤白化病2型(OCA2)是由OCA2基因突变引起的一种常染色体隐性遗传病。虽然OCA2是世界上最常见的白化病形式，但它是一种罕见的疾病(39000人中有1人)。非裔美国少数民族中OCA2的患病率明显较高(1/10，)和美洲原住民后裔(根据载频，1/1,550-2,000的患病率{Yi，2003#1520}，但在一些霍皮族中达到1/200{Woolf，1969#1966})。OCA2会导致皮肤、头发和眼睛色素减少，以及由于视神经走线错误和视网膜发育不良而导致的视力障碍。除了视力丧失外，患皮肤癌的风险大大增加，以及与高度可见的疾病相关的巨大心理社会负担，也是发病率的原因之一。色素沉着是由于黑色素细胞无法产生黑色素，黑色素可以保护皮肤免受紫外线辐射(UV)的伤害，并降低皮肤癌的风险。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OCA2在纳瓦霍人中更常见，他们面临着最大的风险。我们实验室一直在调查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外用药物，该药物将逆转OCA2患者的皮肤色素减退，提供更好的防晒效果，并减轻这种疾病的心理负担。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。我们已经通过筛选逆转培养中小鼠白化黑素细胞色素减退的化合物来确定潜在的药物。在这个试点项目中，我们建议开发一种重建的人类皮肤模型，该模型将在临床试验中让患者服用某种药物之前，深入了解人类的疗效。虽然将在小鼠和人类的黑素细胞中验证“HIT”化合物诱导色素沉着的能力，但这些实验没有解决角质形成细胞的皮肤渗透和新陈代谢问题，这可能会使化合物变得惰性或更糟糕，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无法促进色素沉着的制剂，从而减少动物试验失败的数量。在目标1中，将开发一种重建的皮肤模型，其中将包括来自患有OCA2的小鼠或人类的黑素细胞。该模型将用于目标2，以测试我们最近的化学文库筛选中通过促进白化黑素细胞色素沉着的能力确定的药物的有效性。这些研究将为OCA2的临床试验和最终治疗提供便利。OCA2的治疗将通过减少心理社会耻辱、癌症风险以及未来的视觉缺陷，使患有这种疾病的人在经济上更有成效。此外，开发治疗剂是创造就业机会的重要途径。开发和测试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药物也是如此。该模型的用途将不仅限于OCA2，还可以扩展到任何形式的白化病或黑素细胞相关疾病，从而指数级增加拟议研究的财务影响。OCA2是一种罕见的疾病，会导致皮肤色素沉着不足，由于这种疾病的性质非常明显，会给受影响的个人造成严重的心理痛苦，并使个人非常容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，可以用来测试在培养中逆转OCA2黑素细胞色素表型的化合物的有效性。这种治疗剂将逆转皮肤色素沉着减少，降低皮肤癌风险，并减轻患有这种尚未治愈的疾病的个人的心理社会负担，所有这些都将对患有这种疾病的人产生积极的经济影响，同时为色素沉着障碍的治疗方法的开发提供一条新的管道，这将在学术界和制药行业创造就业机会。

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.