Novel Epigenetic Modifier Inhibitor Drugs for T cell Modulation in Multiple Sclerosis

用于多发性硬化症 T 细胞调节的新型表观遗传修饰抑制剂药物

• 批准号: 9211542
• 负责人: Mireia Guerau-de-Arellano
• 金额: $ 22.09万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211542
• 关键词: Adopted; Arginine; Autoimmune Diseases; Autoimmune Process; Bioavailable; Biological Markers; CD4 Positive T Lymphocytes; Cell Differentiation process; Chronic; Chronic Disease; Clinical; Clinical Management; Data; Demyelinations; Development; Diabetes Mellitus; Disease; Embryonic Development; Enzyme Inhibitor Drugs; Enzymes; Epigenetic Process; Equilibrium; Evaluation; Experimental Autoimmune Encephalomyelitis; Family; Flow Cytometry; Genes; Government; Helper-Inducer T-Lymphocyte; Histones; Home environment; Immunologics; Inflammatory; Institutes; Lead; Legal patent; Lupus; Lymphoid; Mediating; Memory; Methylation; Modeling; Molecular; Multiple Sclerosis; Myelin; Neuraxis; Neurologic; Ohio; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Periodicity; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Primary Progressive Multiple Sclerosis; Process; Proteins; Reaction; Regulatory T-Lymphocyte; Relapse; Rodent Model; Role; Severities; Severity of illness; Signal Transduction; T cell response; T memory cell; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Therapeutic; Therapeutic Effect; Transferase; Universities; Western Blotting; Work; clinical predictors; disability; drug development; enzyme activity; experimental study; immunoregulation; inhibitor/antagonist; mouse model; novel; novel therapeutics; response; small molecule; small molecule inhibitor; young adult

PROJECT SUMMARY/ABSTRACT Multiple Sclerosis (MS), which may present with a relapsing-remitting (RR) or a primary progressive (PP) course, is the leading cause of neurologic disability in young adults. Despite clinical advances, one third of RRMS patients are non-responsive to current therapies, few drugs are available for PPMS, and there is no cure. MS pathogenesis is perpetuated by the cyclical reactivation and expansion of memory myelin-specific T helper (Th) cells that home to the Central Nervous System. Inflammatory T cells with Th1 and Th17 phenotype are pathogenic while regulatory (Treg) and Th2 cells are beneficial. Therefore, strategies that detect and curtail expansion of memory iTc while retaining bTc would provide a significant improvement in MS clinical management. We have recently discovered that a particular epigenetic modifier enzyme is a key molecular regulator of Th1 cell reactivation and Th cell phenotype and that manipulating its enzymatic activity could be therapeutic. We have developed first-in-class inhibitors specific for this enzyme at Ohio State University (patented) and selected two lead inhibitors that preferentially suppress memory Th1 vs. Th2 cell expansion, suppress Th17 cell differentiation and increase Tregs. In addition, a lead inhibitor suppressed pre-established EAE. Overall, these inhibitors have a desirable immunological profile to treat MS and other inflammatory autoimmune diseases. We hypothesize that enzyme activity triggers iTc responses while suppressing bTc responses, promoting clinical disease and propose to define the role of this enzyme as a predictor of disease course and the effects of select enzyme inhibitors on iTc over bTc populations in the EAE model of RR and PP MS. We will 1) determine the extent to which this specific enzyme activity modulates T cell responses and clinical disease in the relapsing-remitting (RR) and chronic Experimental Autoimmune Encephalomyelitis models of MS and 2) determine the extent to which the natural course of enzyme expression/activity predicts clinical disease pattern and severity in the RR and chronic Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS. These studies will determine whether targeting of this enzyme with small molecule inhibitor drugs is a viable approach to treat disease by suppressing myelin- specific inflammatory T cells. In addition, they will determine whether a stable or oscillating pattern of enzyme activity signals a chronic or relapsing-remitting disease course. Therefore, data from these experiments could be used to justify development of similar therapy and/or biomarker/therapy approaches for treating MS and other autoimmune diseases (e.g., diabetes, lupus).

项目概要/摘要 多发性硬化症 (MS)，可能表现为复发缓解型 (RR) 或原发进展型 (PP) 当然，这是年轻人神经系统残疾的主要原因。尽管临床取得了进展，但仍有三分之一 RRMS 患者对当前的治疗没有反应，可用于 PPMS 的药物很少，而且没有 治愈。 MS 发病机制是通过记忆髓磷脂特异性 T 的周期性重新激活和扩张而得以延续的 辅助细胞 (Th) 是中枢神经系统的所在地。具有 Th1 和 Th17 表型的炎症 T 细胞 是致病性的，而调节性细胞 (Treg) 和 Th2 细胞是有益的。因此，检测和限制的策略 扩展记忆 iTc，同时保留 bTc 将显着改善 MS 临床 管理。我们最近发现一种特殊的表观遗传修饰酶是关键 Th1 细胞再激活和 Th 细胞表型的分子调节剂及其酶促调控 活动可能具有治疗作用。我们在俄亥俄州开发了针对这种酶的一流抑制剂 州立大学（专利）并选择了两种优先抑制记忆 Th1 与 Th2 的先导抑制剂 细胞扩张，抑制 Th17 细胞分化并增加 Tregs。此外，铅抑制剂抑制 预先建立的EAE。总体而言，这些抑制剂具有治疗多发性硬化症和 其他炎症性自身免疫性疾病。我们假设酶活性触发 iTc 反应 同时抑制 bTc 反应，促进临床疾病，并建议将该酶的作用定义为 疾病进程的预测因子以及选择的酶抑制剂对 iTc 相对于 bTc 群体的影响 RR 和 PP MS 的 EAE 模型。我们将 1) 确定这种特定酶活性的调节程度 复发缓解型 (RR) 和慢性实验性自身免疫性疾病中的 T 细胞反应和临床疾病 MS 的脑脊髓炎模型和 2) 确定酶自然过程的程度 表达/活性预测 RR 和慢性实验中的临床疾病模式和严重程度 MS 的自身免疫性脑脊髓炎 (EAE) 小鼠模型。这些研究将确定是否针对 这种酶与小分子抑制剂药物是通过抑制髓磷脂来治疗疾病的可行方法 特异性炎症T细胞。此外，他们还将确定酶的稳定模式还是振荡模式 活动标志着慢性或复发缓解型病程。因此，这些实验的数据可以 用于证明治疗多发性硬化症的类似疗法和/或生物标志物/治疗方法的开发合理性 其他自身免疫性疾病（例如糖尿病、狼疮）。