Feasibility Study of Novel Drug Target for Multiple Sclerosis

多发性硬化症新药靶点的可行性研究

基本信息

批准号：
7448468
负责人：
Scott McNear Thacher
金额：
$ 21.02万
依托单位：
ORPHAGEN PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448468
关键词：
Ablation Address Adverse effects Affect Agonist Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Autoimmune Process Autoimmune encephalitis Bioavailable Biological Availability C57BL/6 Mouse CD4 Positive T Lymphocytes Caring Categories Cell Differentiation process Cell Survival Cells Cellularity Class Clinical Data Development Disease Drug Delivery Systems Encephalomyelitis End Point Family Feasibility Studies Genetic Genetic Transcription Goals Grant Helper-Inducer T-Lymphocyte Human Immune Immune system In Vitro Incidence Individual Inflammation Inflammatory Interleukin-17 Knockout Mice Knowledge Laboratories Lead Ligands Mediating Medical Research Modeling Multiple Sclerosis Mus Nuclear Nuclear Hormone Receptors Nuclear Orphan Receptor Nuclear Receptors Orphan Pain Paralysed Pathogenesis Pathology Peptides Pharmaceutical Preparations Pharmacology Phase Phenotype Positioning Attribute Productivity Protein Isoforms Public Health RNA Splicing Regulation Retinoids Rodent Rodent Model Role Safety Small Business Funding Mechanisms Small Business Innovation Research Grant Specificity Steroids Suggestion Symptoms T-Lymphocyte Testing Therapeutic Therapeutic Agents Thyroid Gland Transfection Upper arm Woman Work base cost cytokine design immune function in vivo inhibitor/antagonist interleukin-23 member men mouse model neuroinflammation novel novel therapeutics oligodendrocyte-myelin glycoprotein peripheral blood pre-clinical small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): A novel class of T helper cell, distinct from TH1 and TH2 cells, has been implicated in the development of murine experimentally-acquired encephalomyelitis (EAE), a model of multiple sclerosis (MS). This effector T cell, termed a TH-17 cell, is characterized by release of the highly pro-inflammatory cytokine interleukin 17 (IL- 17). Deficiency of the TH-17 survival factor IL-23, or of IL-17 itself, blocks or substantially inhibits development of EAE and several other autoimmune diseases in mice. The nuclear transcription factor ROR?, an orphan member of the steroid-thyroid-retinoid family of nuclear hormone receptors, is required for differentiation of TH-17 cells. We recently identified ROR? antagonists and showed that these specifically inhibit cytokine- mediated TH-17 but not TH1 formation from na¿ve mouse CD4+ T cells in culture. The major objectives of this proposal are to design an ROR? lead antagonist suitable for in vivo studies and to test the hypothesis that such a compound can inhibit the induction of EAE in a rodent model of MS. In Aim 1, more potent ROR? antagonists will be synthesized based on compounds already identified by the applicant. A selective and bioavailable compound will be chosen for further work. In Aim 2, the lead ROR? antagonist will be tested in EAE and its effect on TH-17 development investigated. In Aim 3, we determine whether ROR? antagonists inhibit IL-17 expression in human peripheral blood T cells, confirming a common pharmacology of ROR? ligands in mouse and human. If these feasibility studies successfully demonstrate inhibition of symptoms in rodent EAE by an ROR? antagonist and regulation of IL-17 expression in isolated human T cells, we plan in Phase II to initiate discovery, development and testing of a pre-clinical drug candidate. The long-term goal of this work is to create an entirely new class of orally-bioavailable, anti-inflammatory drug for MS and other forms of autoimmune disease. RELEVANCE TO PUBLIC HEALTH Multiple sclerosis (MS) is a painful and crippling disease that affects an estimated 350,000 individuals in the U.S. alone. The incidence among women is twice that of men. The annual cost in terms of direct care and lost productivity has been estimated at $7 billion/year. Therapeutic treatments for MS are limited and most have serious side effects. Recent basic medical research has described a novel actor in the immune system: a specialized immune cell that has a central causative role in animal models of MS. By developing drugs that selectively target this new category of immune cell, we have the opportunity to develop safer therapies for MS.

描述（由申请人提供）：一种不同于 TH1 和 TH2 细胞的新型 T 辅助细胞，与小鼠实验性获得性脑脊髓炎（EAE）（一种多发性硬化症（MS）模型）的发展有关。细胞，称为 TH-17 细胞，其特征是释放高度促炎细胞因子白细胞介素 17（IL-17 缺乏）。 TH-17 生存因子 IL-23 或 IL-17 本身可阻断或显着抑制小鼠 EAE 和其他几种自身免疫性疾病的发展。核激素受体是 TH-17 细胞分化所必需的，我们最近发现了 ROR? 拮抗剂，并表明它们特异性抑制细胞因子介导的 TH-17，但不能抑制 na¿该提案的主要目的是设计一种适合体内研究的 ROR? 主要拮抗剂，并测试这种化合物可以在 MS 啮齿动物模型中抑制 EAE 的诱导。 1、将基于申请人已鉴定的化合物合成更有效的ROR 拮抗剂，将选择一种选择性的和生物可利用的化合物进行进一步的研究，将在EAE 中测试主要的ROR 拮抗剂及其效果。在目标 3 中，我们确定 ROR? 拮抗剂是否抑制人外周血 T 细胞中的 IL-17 表达，从而证实 ROR? 配体在小鼠和人类中的共同药理学。通过 ROR 拮抗剂治疗啮齿类动物 EAE 的症状并调节分离的人 T 细胞中的 IL-17 表达，我们计划在第二阶段启动临床前候选药物的发现、开发和测试，这是这项工作的长期目标。是创造一类全新的口服生物可利用的抗炎药物，用于治疗多发性硬化症和其他形式的自身免疫性疾病。与公众健康的相关性多发性硬化症 (MS) 是一种痛苦且致残的疾病，仅在美国就有 350,000 人受到影响，女性的发病率是男性的两倍，据估计，每年的直接护理费用和生产力损失。每年 70 亿美元的治疗费用是有限的，并且大多数都有严重的副作用。最近的基础医学研究描述了免疫系统中的一个新角色：一种具有中枢的特殊免疫细胞。通过开发选择性针对这一新类别免疫细胞的药物，我们有机会开发更安全的多发性硬化症治疗方法。