Oklahoma ACE: Molecular Deconstruction of Autoimmune Disease to Aid Clinical Trial Success

俄克拉荷马州 ACE：自身免疫性疾病的分子解构有助于临床试验的成功

• 批准号: 10608163
• 负责人: JUDITH A JAMES
• 金额: $ 8.74万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608163
• 关键词: Acceleration; Address; Age Years; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell therapy; B-Cell Activation; B-Lymphocytes; Basic Science; Biological; Biological Testing; Biology; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Certification; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; Collection; Complex; Data; Development; Disease; Education; Environment; FDA approved; Flare; Fostering; Foundations; Gene Expression Profiling; Genetic; Goals; Heterogeneity; Human Resources; Immune; Immunologics; Immunologist; Immunophenotyping; Immunosuppressive Agents; Inflammation; Inflammatory; Injections; Intramuscular; Lead; Leadership; Leukocyte Elastase; Lupus; Manuscripts; Mediator; Medlone 21; Methodology; Molecular; Molecular Disease; Neuromyelitis Optica; Oklahoma; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Polypharmacy; Population; Prediction of Response to Therapy; Productivity; Publications; Randomized; Relapse; Research; Research Infrastructure; Research Personnel; Resistance; Role; Rural Community; Safety; Scientist; Serology; Site; Sjogren' s Syndrome; Steroids; Subgroup; Systemic Lupus Erythematosus; Tacrolimus; Testing; Therapeutic; Thrombotic Thrombocytopenic Purpura; Translations; Woman; Work; active method; alpha 1-Antitrypsin; base; biobank; cohort; design; disability; disease heterogeneity; disorder control; drug repurposing; effectiveness evaluation; effectiveness testing; efficacy evaluation; experience; fortification; improved; indexing; innovation; insight; minority communities; molecular subtypes; monocyte; multidisciplinary; mycophenolate mofetil; neutrophil; novel; novel therapeutics; pre-clinical; predicting response; programs; prospective test; recruit; relapse risk; response; single cell technology; success; synergism; targeted treatment; therapeutic development; therapy development; trial design

Project Summary The Oklahoma ACE (OACE) strives to understand the biology of autoimmune diseases through interdisciplinary, collaborative research that integrates clinical and basic questions. This prior ACE work has led to 128 publications, including 42 with authors from 2 or more ACEs, leadership of a previous and ongoing ACE clinical trial and lead or near lead recruitment in three ACE trials while a Basic ACE. We build on this expertise through this UM1 Clinical ACE submission. Although significant progress in unveiling mechanisms of autoimmune disease pathogenesis has been made, development of targeted therapies is critically lacking. For autoimmune disease therapeutic development to succeed and patient outcomes to improve, deepened understanding of molecular disease heterogeneity, therapeutic pharmacobiology and improved trial designs are needed. The Oklahoma ACE will pursue a novel, comprehensive theme of accelerating discovery and translation by deconstructing molecular heterogeneity to enrich for patients with common molecular pathways, partnered with repurposed therapies from other fields and novel trial designs which eliminate confounding background polypharmacy, to address these unmet needs. Our primary clinical project utilizes our innovative SLE trial design which uses serial depomedrol injections to suppress disease, halting of background immunosuppressive drugs to provide a more pristine environment to test the effectiveness of mycophenolate mofetil with or without add-on of tacrolimus to suppress SLE activity. Partnered mechanistic studies will test our soluble mediator flare index and other select activated immune cell subsets for the ability to predict upcoming flare, as well as to test specific hypotheses of MMF response/resistance and of SLE disease flare mechanisms. Preliminary data in our alternate clinical project has found critical roles of neutrophils in neuromyelitis optica, a complex autoimmune disease where up to 40% of patients have continual relapse and damage even with treatment with B cell depleting therapies and steroids. Pre-clinical work from this team has shown efficacy in two animal models of alpha-1 anti-trypsin, which inhibits neutrophil elastase. This first-in-NMO study will assess effectiveness and safety, as well as mechanistic studies which test biologic mechanisms of treatment, predictors of response and molecular mechanisms of NMO flare. Our collaborative project deconstructs molecular heterogeneity and associated pathogenic mechanisms of disease in subgroups of SLE patients. Building on preliminary data which identifies seven molecular subsets by gene expression profiling, soluble mediators and autoantibodies, proposed studies will test hypotheses of specific molecular mechanisms through deep immunophenotyping and single cell technologies such as scRNAseq, CITE-seq, CyTOF and ChipCytometry. These projects, facilitated by our Admin Core, will study fundamental aspects of autoimmunity and conduct focused clinical trials for SLE, NMO and other autoimmune diseases. Our Center will also continue to collaborate and recruit for the ACE Network.

项目摘要 俄克拉荷马州ACE(OACE)致力于通过 整合临床和基础问题的跨学科协作研究。这项先前的ACE工作具有 导致了128份出版物，其中42份的作者来自2个或更多的王牌，领导着以前的和正在进行的 ACE临床试验和在三个ACE试验中招募领队或接近领队，同时进行基本的ACE。我们以此为基础 通过这份UM1临床ACE提交获得专业知识。尽管在揭示机制方面取得了重大进展 自身免疫性疾病的发病机制已经确定，但缺乏靶向治疗的发展。为 自身免疫性疾病治疗发展取得成功，患者预后改善，深化 了解分子疾病的异质性、治疗药物生物学和改进的试验设计 都是需要的。俄克拉荷马州ACE将追求一个新颖、全面的主题，即加速发现和 通过解构分子异质性来丰富具有共同分子途径的患者的翻译， 与其他领域的重新调整用途的疗法和消除混淆的新颖试验设计合作 背景多药房，以解决这些未得到满足的需求。 我们的主要临床项目采用了我们创新的系统性红斑狼疮试验设计，该试验设计使用了系列去甲美洛尔 注射以抑制疾病，停止背景免疫抑制药物提供更纯净的 环境测试霉酚酸酯在添加或不添加他克莫司的情况下对 抑制系统性红斑狼疮活动。合作的机理研究将测试我们的可溶性介体耀斑指数和其他选择 激活的免疫细胞亚群，用于预测即将到来的耀斑以及测试特定的假设 MMF反应/耐药和SLE疾病发病机制。我们替代临床的初步数据 Project发现中性粒细胞在视神经脊髓炎中起关键作用，视神经脊髓炎是一种复杂的自身免疫性疾病， 即使用B细胞去除疗法治疗，也有40%的患者持续复发和损害。 类固醇。该团队的临床前工作已经在两种α-1抗胰蛋白酶的动物模型中显示出有效性， 抑制中性粒细胞弹性蛋白酶。这项首创的NMO研究将评估有效性和安全性，以及 测试治疗的生物机制、反应的预测因素和分子的机制研究 动校耀斑的形成机制。我们的合作项目解构了分子的异质性和关联 系统性红斑狼疮患者亚组的发病机制。以初步数据为基础，确定 通过基因表达谱、可溶性介体和自身抗体的七个分子亚群，拟议的研究 将通过深度免疫表型和单细胞来检验特定分子机制的假说 诸如scRNAseq、Cite-seq、CyTOF和芯片细胞术等技术。这些项目，由我们的 管理核心，将研究自身免疫的基本方面，并针对SLE、NMO进行重点临床试验 以及其他自身免疫性疾病。我们的中心还将继续为ACE网络进行协作和招聘。