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.

摘要 药物开发是一个效率低下且昂贵的过程，其中药物可能会在后期失败。 III期临床试验或由于治疗后出现严重副作用的非预期表现 释放到市场上。例如，Dupilumab，一种白细胞介素-4受体拮抗剂， , 特应性皮炎（AD）通常引起不良反应，如角膜炎、眼瘙痒和 眼睛干涩和鼻咽炎。AD是最常见的慢性皮肤炎症之一 疾病，影响全球15-20%的儿童和1-3%的成人。AD是一种复杂的 和多因素疾病，AD发病机制是由遗传因素驱动的，以及 by environmental环境cues线索.丝聚蛋白（FLG）基因被认为在肿瘤的发生发展中起着至关重要的作用。 AD的病理生理学此外，AD病变与葡萄球菌之间存在联系 Aureus（S. Aureus）定殖，因为观察到约90%的AD患者是 与S.金黄色葡萄球菌感染率增高; Aureus负荷与 疾病在受影响的皮肤上爆发。已经开发了动物模型来描述AD 然而，对于发病机制和临床前药物测试，这些模型不能忠实地 概括了多效性疾病表型，因为小鼠不能自发地 发展AD。同样地， AD的体外模型不重现 之间的串扰 不同器官参与AD。在这个项目中，我们将建立一个功能网络， 包括皮肤、角膜和鼻组织的三个组织系统，以及循环系统， T细胞和微生物群（Sk-Co-Na-T-MB）来模拟AD。该平台将实现多- 因子方法来描述AD发病机制，以及提供前所未有的 在遗传学定义的AD队列中检测药物毒性/疗效的预测能力 患者的iPSC。我们将通过检查几种药物的疗效/毒性来验证该平台。 FDA批准的和新出现的AD药物，包括Dupilumab（一种白细胞介素-4受体 拮抗剂）、阿普斯特（一种PDE 4抑制剂）和托法替尼（一种泛JAK抑制剂）。最后， 我们还将研究遗传和环境风险因素的复合效应 （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，使我们能够进行临床- 特应性皮炎的相关和患者特异性临床试验。