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Clinical Trials in a Dish Using a Personalized Multi-Tissue Platform for Atopic Dermatitis

Clinical Trials in a Dish Using a Personalized Multi-Tissue Platform for Atopic Dermatitis
使用个性化多组织平台进行特应性皮炎的临床试验
批准号:
10038233
负责人:
Angela M Christiano
金额:
$60.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-23 至 2022-08-31

项目摘要

项目成果

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中文摘要
翻译
摘要 药物开发是一个低效和昂贵的过程,在这个过程中,药物可能会在后期失败 3期临床试验或由于以下严重副作用的意外表现 投放市场。例如,白介素4受体拮抗剂Dupilumab , 特应性皮炎(AD),通常会引起不良反应,如角膜炎,眼睛瘙痒和 干眼症和鼻咽炎。AD是最常见的慢性炎症性皮肤之一 疾病,影响到全世界15%-20%的儿童和1%-3%的成年人。广告是一种复杂的东西 和多因素疾病,AD的发病是由遗传因素以及 由环境线索决定。微丝蛋白(flaggrin,flg)基因被认为在 阿尔茨海默病的病理生理学。此外,阿尔茨海默病和葡萄球菌之间也有联系 金黄色葡萄球菌(S.aureus)定植,因为据观察,~90%的AD患者 金黄色葡萄球菌在皮损中定植,金黄色葡萄球菌载量增加与 疾病在受影响的皮肤上爆发。已经开发出动物模型来描绘AD 然而,对于发病机制和临床前药物测试,这些模型并不可靠。 重述多效性疾病的表型,因为小鼠不自发地 开发AD。同样, 阿尔茨海默病体外模型不能概括 两个人之间的串扰 参与AD的不同器官。在这个项目中,我们将建立一个功能网络, 包括皮肤、角膜和鼻部组织以及循环在内的三个组织系统 T细胞和微生物区系(Sk-Co-Na-T-MB)建立AD模型。该平台将实现多个 用析因方法来描述AD的发病机制,以及提供前所未有的 在遗传定义的AD队列中检测药物毒性/疗效的预测能力 病人的ipscs。我们将通过检查以下几种药物的疗效/毒性来验证该平台 FDA批准的和新兴的AD药物,包括Dupilumab(一种白细胞介素4受体 拮抗剂)、阿普米司特(PDE4抑制剂)和托法替尼(PAN-JAK抑制剂)。最后, 我们还将调查遗传和环境风险因素的复合效应。 (微生物区系和Flg突变),我们的AD患者队列将反映性别和 接受AD药物治疗的患者群体的种族多样性,使我们能够在临床上- 特应性皮炎DISH的相关和针对患者的临床试验。
英文摘要
ABSTRACT Drug development is an inefficient and expensive process, in which a drug can fail late in phase 3 clinical trials or due to the unanticipated manifestation of severe side-effects after release onto the market. For example, Dupilumab, an Interleukin-4 receptor antagonist for , atopic dermatitis (AD), often causes adverse reactions such as keratitis, eye pruritus and dry eyes and nasopharyngitis. AD is one of the most common chronic inflammatory skin diseases, affecting 15-20% of children and 1-3% of adults worldwide. AD is a complex and multifactorial disease, and AD pathogenesis is driven by genetic factors, as well as by environmental cues. The filaggrin (FLG) gene is believed to play a crucial role in the pathophysiology of AD. Moreover, there is a link between AD lesions and Staphylococcus Aureus (S. Aureus) colonization, since it is observed that ~90% of AD patients are colonized with S. aureus in lesional skin, and increased S. Aureus loads correlate with disease flares in the affected skin. Animal models have been developed to delineate AD pathogenesis and for preclinical drug testing, however, these models fall short of faithfully recapitulating the pleiotropic disease phenotypes since mice do not spontaneously develop AD. Likewise, in vitro models of AD do not recapitulate the crosstalk between different organs involved in AD. In this project, we will establish a functional network of three tissue systems comprised of skin, cornea and nasal tissues, as well as circulating T cells and microbiota (Sk-Co-Na-T-MB) to model AD. This platform will enable a multi- factorial approach to delineating AD pathogenesis, as well as provide unprecedented predictive power to detect drug toxicity/efficacy in a genetically-defined cohort of AD patients iPSCs. We will validate the platform by examining the efficacy/toxicity of several FDA-approved and emerging AD drugs, including Dupilumab (an Interleukin-4 receptor antagonist), Apremilast (a PDE4 inhibitor) and Tofacitinib (a pan-JAK inhibitor). Finally, we will also investigate the compounding effects of genetic and environmental risk factors (microbiota and FLG mutations), and our AD patient cohort will reflect the gender and ethnic diversity of patient populations receiving AD drugs, allowing us to perform clinically- relevant and patient-specific Clinical Trials in a Dish for Atopic Dermatitis.
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