Feasibility Study of Novel Drug Target for Multiple Sclerosis

描述（由申请人提供）：一种不同于TH 1和TH 2细胞的新型T辅助细胞与小鼠实验性获得性脑脊髓炎（EAE）（多发性硬化症（MS）模型）的发生有关。这种效应T细胞称为TH-17细胞，其特征在于释放高度促炎细胞因子白细胞介素17（IL- 17）。TH-17存活因子IL-23或IL-17本身的缺乏阻断或基本上抑制小鼠中EAE和几种其它自身免疫性疾病的发展。核转录因子ROR？，是核激素受体的类固醇-甲状腺-类维生素A家族的孤儿成员，是TH-17细胞分化所必需的。我们最近发现了罗？拮抗剂，并显示这些特异性抑制细胞因子介导的TH-17，但不抑制培养中幼稚小鼠CD 4 + T细胞的TH 1形成。这项建议的主要目标是设计一个ROR？铅拮抗剂适合于在体内研究，并测试的假设，这种化合物可以抑制诱导EAE的啮齿动物模型MS。在目的1，更有效的ROR？拮抗剂将基于申请人已经鉴定的化合物合成。选择性和生物可利用的化合物将被选择用于进一步的工作。在目标2中，领先的ROR？拮抗剂将在EAE中进行测试，并研究其对TH-17发育的影响。在目标3中，我们确定是否ROR？拮抗剂抑制IL-17在人外周血T细胞的表达，证实了ROR？在小鼠和人中的配体。这些可行性研究是否成功证明ROR可抑制啮齿动物EAE的症状？拮抗剂和调节IL-17在分离的人T细胞中的表达，我们计划在II期开始发现，开发和测试临床前候选药物。这项工作的长期目标是为MS和其他形式的自身免疫性疾病创造一种全新的口服生物可利用的抗炎药物。 多发性硬化症（MS）是一种疼痛和致残性疾病，仅在美国就影响了大约35万人。妇女的发病率是男子的两倍。直接护理和生产力损失方面的年度成本估计为70亿美元/年。MS的治疗方法是有限的，大多数都有严重的副作用。最近的基础医学研究已经描述了免疫系统中的一种新演员：一种专门的免疫细胞，在MS的动物模型中起着重要的致病作用。通过开发选择性靶向这种新类别免疫细胞的药物，我们有机会为MS开发更安全的疗法。

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.