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（由适用提供）：一种与Th1和Th2细胞不同的新型T辅助细胞在经验丰富的脑脊髓炎（EAE）的发展中实施，这是多发性硬化症（MS）的模型。该效应T细胞称为TH-17细胞，其特征是释放高度促炎性细胞因子白介素17（IL-17）。 TH-17生存因子IL-23或IL-17本身的缺乏，可以阻止或极大地抑制EAE的发育和小鼠中其他几种自身免疫性疾病。核转录因子是核骑术受体的立体 - 甲状腺类母性家族的孤儿成员，是Th-17细胞的分化所必需的。我们最近确定了ROR？拮抗剂，并表明这些特别抑制了培养中Na¿ve小鼠CD4+ T细胞的细胞因子介导的Th-17，但不抑制Th1的形成。该提案的主要目的是设计ROR？铅拮抗剂适合体内研究，并检验这样的假设，即这种化合物可以抑制MS啮齿动物模型中EAE的诱导。在AIM 1中，更多的潜在ROR？将根据适用的化合物合成拮抗剂。将选择一种选择性和生物利用化合物进行进一步的工作。在AIM 2中，主角？对抗者将在EAE中进行测试及其对研究的TH-17发展的影响。在AIM 3中，我们确定是否ROR？拮抗剂抑制人类外周血T细胞中IL-17的表达，证实了ROR的常见药物？小鼠和人类的配体。如果这些可行性研究成功地证明了ROR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期中启动临床前药物候选者的发现，开发和测试。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建一类全新的口服可提供的抗炎药。与公共卫生多发性硬化症（MS）相关的是一种痛苦而残酷的疾病，仅在美国就影响了35万人。女性之间的事件是男性的两倍。直接护理和生产率损失的年度成本估计为70亿美元/年。 MS的治疗治疗有限，大多数具有严重的副作用。最近的基本医学研究描述了免疫系统中的一个新演员：一种专门的免疫核管，在MS动物模型中具有中心作用。通过开发有选择地针对这一新类别的免疫核物的药物，我们有机会为MS开发更安全的疗法。