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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

基本信息

批准号：
10396550
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
项目类别：
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/10396550
关键词：
Address Age-Years Animal Model Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocytes Basic Science Biological Biological Products 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&apos s Syndrome Steroids Subgroup Systemic Lupus Erythematosus Tacrolimus Testing Therapeutic Thrombotic Thrombocytopenic Purpura 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

项目摘要

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.

项目总结