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

项目摘要 俄克拉荷马州ACE（OACE）致力于了解自身免疫性疾病的生物学， 跨学科的合作研究，整合临床和基础问题。ACE的这一前期工作 导致128篇出版物，其中42篇作者来自2个或更多ACE，领导了以前和正在进行的 ACE临床试验和三项ACE试验中的电极导线或近电极导线招募，而基础ACE。我们以此为基础 通过本次UM 1临床ACE提交的专业知识。虽然在揭示联合国系统的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，靶向治疗的发展是严重缺乏。为 自身免疫性疾病的治疗发展取得成功，患者的结局得到改善， 了解分子疾病异质性、治疗药物生物学和改进试验设计 是必要的。俄克拉荷马州ACE将追求一个新颖的，全面的主题，加速发现， 翻译通过解构分子异质性来富集患者共有的分子通路， 与来自其他领域的重新设计的疗法和消除混淆的新颖试验设计合作 背景多药疗法，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，使用连续的地普美醇 注射抑制疾病，停止背景免疫抑制药物，以提供更原始的 环境，以测试霉酚酸酯与或不与他克莫司添加的有效性， 抑制SLE活性。合作机制研究将测试我们的可溶性介质耀斑指数和其他选择 激活免疫细胞亚群的能力，以预测即将到来的耀斑，以及测试特定的假设， MMF反应/耐药性和SLE疾病发作机制。我们的替代临床试验的初步数据 一个项目发现了嗜中性粒细胞在视神经肌萎缩症中的关键作用，这是一种复杂的自身免疫性疾病， -40%的患者即使用B细胞耗竭疗法治疗也有持续复发和损伤， 类固醇.该团队的临床前工作已经在两种α-1抗胰蛋白酶动物模型中显示出疗效， 其抑制中性粒细胞弹性蛋白酶。这项首次进行的NMO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、反应的预测因子和分子生物学机制。 NMO耀斑机制我们的合作项目解构分子异质性和相关的 SLE患者亚群的致病机制。根据初步数据， 通过基因表达谱、可溶性介质和自身抗体，拟定研究的7个分子亚组 将通过深层免疫表型和单细胞检测来检验特定分子机制的假设。 技术如scRNAseq、CITE-seq、CyTOF和ChipCytometry。这些项目由我们的 管理核心，将研究自身免疫的基本方面，并为SLE，NMO进行重点临床试验 和其他自身免疫性疾病。我们的中心也将继续合作，并为ACE网络招募。

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.