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: 10158411
• 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/10158411
• 关键词: Address; Age-Years; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Basic Science; Biological; Biological Testing; Biology; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; Collection; Complex; Data; Development; Disease; 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 of activation protein; 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; Translations; Trypsin; Woman; Work; active method; alpha 1-Antitrypsin; base; biobank; cohort; design; disability; disease heterogeneity; disorder control; effectiveness evaluation; effectiveness testing; experience; 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.

项目概要 俄克拉荷马州 ACE (OACE) 致力于通过以下方式了解自身免疫性疾病的生物学： 整合临床和基础问题的跨学科合作研究。之前的 ACE 工作有 发表了 128 篇出版物，其中 42 篇的作者来自 2 个或更多 ACE，是先前和正在进行的 ACE 临床试验以及三个 ACE 试验中的主要或接近主要招募，以及基本 ACE。我们以此为基础 通过此 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明确，但目前严重缺乏靶向治疗的开发。为了 自身免疫性疾病治疗方法的成功开发和患者治疗结果的改善、深化 了解分子疾病异质性、治疗药理学和改进的试验设计 需要。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进行翻译，以丰富具有共同分子途径的患者， 与其他领域的重新利用的疗法和新颖的试验设计合作，消除了混杂因素 背景多药治疗，以解决这些未满足的需求。 我们的主要临床项目利用我们创新的 SLE 试验设计，该设计使用系列 depomedrol 注射以抑制疾病，停止使用背景免疫抑制药物以提供更原始的状态 测试霉酚酸酯在添加或不添加他克莫司的情况下的有效性的环境 抑制 SLE 活动。合作机制研究将测试我们的可溶性介体耀斑指数和其他选择 激活的免疫细胞子集能够预测即将到来的爆发，以及测试特定的假设 MMF 反应/抵抗和 SLE 疾病发作机制。我们的替代临床的初步数据 项目发现中性粒细胞在视神经脊髓炎中发挥关键作用，视神经脊髓炎是一种复杂的自身免疫性疾病 即使使用 B 细胞耗竭疗法进行治疗，仍有 40% 的患者出现持续复发和损伤 类固醇。该团队的临床前工作已在两种 alpha-1 抗胰蛋白酶动物模型中显示出功效， 它抑制中性粒细胞弹性蛋白酶。这项 NMO 首次研究将评估有效性和安全性，以及 机制研究，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。我们的合作项目解构了分子异质性和相关的 SLE 患者亚组疾病的致病机制。根据初步数据确定 根据基因表达谱、可溶性介质和自身抗体划分的七个分子亚群，拟议的研究 将通过深度免疫表型分析和单细胞测试特定分子机制的假设 scRNAseq、CITE-seq、CyTOF 和 ChipCytometry 等技术。这些项目由我们的推动 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 和其他自身免疫性疾病。我们中心还将继续与 ACE 网络合作并招募人员。