Feasibility Study of Novel Drug Target for Multiple Sclerosis

描述(由申请人提供)：一种不同于TH1和TH2细胞的新型辅助性T细胞与多发性硬化症(MS)模型--小鼠实验性获得性脑脊髓炎(EAE)的发生有关。这种效应T细胞被称为TH-17细胞，其特征是释放高度促炎的细胞因子白介素17(IL-17)。缺乏TH-17生存因子IL-23或IL-17本身，可阻止或基本上抑制小鼠EAE和其他几种自身免疫性疾病的发展。核转录因子ROR？是类固醇-甲状腺-维甲酸核激素受体家族的孤儿成员，是TH-17细胞分化所必需的。我们最近确认了ROR？拮抗剂，并表明这些特异性地抑制细胞因子介导的TH-17，但不能抑制培养中的小鼠CD4+T细胞的TH1的形成。这项提案的主要目标是设计一项RoR？适合体内研究的先导拮抗剂，并验证这样的化合物可以抑制MS啮齿动物模型EAE诱导的假说。拮抗剂将根据申请人已经确定的化合物进行合成。将选择一种选择性和生物可用的化合物进行进一步的研究。在《目标2》中，领跑者是谁？拮抗剂将在EAE中进行测试，并研究其对TH-17开发的影响。在目标3中，我们确定ROR？拮抗剂抑制人外周血T细胞IL-17的表达，证实了ROR？的常见药理作用。小鼠和人类体内的配体。如果这些可行性研究成功地证明了ROR对啮齿动物EAE症状的抑制作用？为了拮抗和调节分离的人T细胞中IL-17的表达，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。这项工作的长期目标是创造一种全新的口服生物利用型抗炎药物，用于多发性硬化症和其他形式的自身免疫性疾病。 与公共卫生相关的多发性硬化症(MS)是一种痛苦而严重的疾病，仅在美国就有大约35万人受到影响。女性的发病率是男性的两倍。在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。多发性硬化症的治疗方法有限，而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种新因素：一种在MS动物模型中具有核心致病作用的特殊免疫细胞。通过开发有选择性地针对这一新类别免疫细胞的药物，我们有机会为MS开发更安全的治疗方法。

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.