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: $ 60万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038233
• 关键词: 3-Dimensional; Adult; Adverse reactions; Affect; Age; Alleles; Animal Model; Atopic Dermatitis; Biological; Cells; Child; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Colony-Forming Units Assay; Complex; Conduct Clinical Trials; Cornea; Cues; Development; Disease; Disease model; Drug toxicity; Endothelium; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Etiology; Eye; FDA approved; Failure; Fibroblasts; Flare; Functional disorder; Gender; Gene Dosage; Genes; Genetic; Genetic Risk; Genotype; Immune; In Vitro; Inflammatory; Interleukin 4 Receptor; Keratitis; Lesion; Link; Methods; Microfluidics; Modeling; Monitor; Mus; Mutation; Nasopharyngitis; Nose; Organ; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Phenotype; Play; Process; Pruritus; Race; Risk Factors; Role; Sampling; Series; Skin; Source; Staphylococcus aureus; Swelling; System; T-Lymphocyte; Th2 Cells; Tissues; Toxic effect; analytical method; cell type; chronic inflammatory skin; clinical development; clinically relevant; cohort; cytokine; design; disease phenotype; dosage; drug development; drug efficacy; drug testing; ethnic diversity; experience; eye dryness; falls; filaggrin; gender diversity; imaging modality; in vitro Model; induced pluripotent stem cell; inhibitor/antagonist; keratinocyte; microbiota; novel; novel drug class; patient population; pre-clinical; response; side effect; skin disorder; skin lesion; skin microbiota; small molecule; temporal measurement; transcriptome sequencing

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.

抽象的 药物开发是一个效率低下且昂贵的过程，在该过程中，药物可能会迟到 第三阶段临床试验或由于在 释放到市场。例如，Dupilumab，一种白介素-4受体拮抗剂 ，，，， 特应性皮炎（AD）通常会引起不良反应，例如角膜炎，瘙痒和 干眼和鼻咽炎。广告是最常见的慢性炎症皮肤之一 疾病影响了15-20％的儿童和1-3％的全球成年人。广告是一个复杂的 以及多因素疾病以及AD发病机理是由遗传因素驱动的， 通过环境提示。菲尔格林（FLG）基因被认为在 AD的病理生理学。此外，广告病变和葡萄球菌之间存在联系 金黄色葡萄球菌（金黄色葡萄球菌）定植，因为观察到约90％的AD患者是 在病变的皮肤中用金黄色葡萄球菌定殖，并增加金黄色葡萄球菌载荷与 疾病在受影响的皮肤中耀斑。已经开发了动物模型来描述广告 然而，发病机理和临床前药物测试，这些模型忠实地降低了 概括多效性疾病表型，因为小鼠不会自发 开发广告。同样地， AD的体外模型不概括 之间的串扰 广告中涉及的不同器官。在这个项目中，我们将建立一个功能网络 三个组织系统由皮肤，角膜和鼻组织以及循环 T细胞和微生物群（SK-CO-NA-T-MB）以建模AD。该平台将使多个 描述AD发病机理的阶乘方法，并提供前所未有的 在遗传定义的AD队列中检测药物毒性/功效的预测能力 患者IPSC。我们将通过检查几个的功效/毒性来验证平台 FDA批准和新兴的广告药物，包括dupilumab（白介素-4受体 拮抗剂），Apremilast（PDE4抑制剂）和Tofacitinib（pan-jak抑制剂）。最后， 我们还将研究遗传和环境风险因素的复合作用 （微生物群和FLG突变），我们的AD患者队列将反映性别和 接受AD药物的患者人群的种族多样性，使我们能够在临床上进行 在特应性皮炎的菜肴中进行的相关和患者特异性临床试验。