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）努力通过自身免疫性疾病的生物学来通过 跨学科的协作研究，整合临床和基本问题。这项先前的王牌工作有 导致了128个出版物，其中包括来自2个或更多王牌的作者的42个出版物，以前的和正在进行的领导 ACE临床试验和铅或接近铅招募三个ACE试验，而基本ACE。我们以此为基础 通过此UM1临床ACE提交的专业知识。尽管在揭幕机制方面取得了重大进展 已经产生了自身免疫性疾病发病机理，靶向疗法的发展严重缺乏。为了 自身免疫性疾病的治疗性发育，并取得成功的患者结局，以改进，加深 了解分子疾病异质性，治疗性药物生物学和改进的试验设计 需要。俄克拉荷马州的王牌将追求一个新颖，全面的发现主题 通过解构分子异质性来翻译，以富含常见分子途径的患者， 与其他领域的重新利用疗法和新颖的试验设计合作，消除了混乱 背景多剂量，以满足这些未满足的需求。 我们的主要临床项目利用了使用串行DepomeDrol的创新SLE试验设计 注射以抑制疾病，停止背景免疫抑制药物以提供更原始的 环境测试霉酚酸酯莫菲蒂的有效性，有或没有他克莫司的附加效果 抑制SLE活动。合作的机械研究将测试我们的可溶性调解人耀斑指数和其他选择 激活的免疫细胞亚群，以预测即将到来的耀斑的能力，并测试特定假设 MMF反应/抗性和SLE病耀斑机制。我们替代临床中的初步数据 项目发现，中性粒细胞在神经霉炎Optica（一种复杂的自身免疫性疾病）中的关键作用，其中 对于40％的患者，即使用B细胞耗尽疗法的治疗以及 类固醇。该团队的临床前工作显示了两种α-1抗tribypsin的动物模型的功效， 抑制中性粒细胞弹性酶。这项NMO的第一项研究将评估有效性和安全性，以及 机械研究测试治疗的生物学机制，反应预测因子和分子 NMO耀斑的机制。我们的协作项目解构了分子异质性和相关性 SLE患者亚组中疾病的致病机制。基于标识的初步数据 拟议研究提出的研究 将通过深层免疫表型和单细胞检验特定分子机制的假设 诸如scrnaseq，cite-seq，cytof和chipcytermetry之类的技术。这些项目，由我们的 管理员核心将研究自身免疫性的基本方面，并为SLE，NMO进行集中临床试验 和其他自身免疫性疾病。我们的中心还将继续为ACE网络合作和招募。