High throughput screening and in vivo testing of drugs to enhance remyelination

增强髓鞘再生药物的高通量筛选和体内测试

• 批准号: 8619381
• 负责人: ROBERT H. MILLER
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619381
• 关键词: Address; Adult; Affect; Animal Model; Autoimmune Process; Axon; Biological Assay; Biological Models; Brain; Cell Culture Techniques; Cell Differentiation process; Cell Maturation; Clinical; Clinical Trials; Collection; Complex; Cultured Cells; Data; Demyelinating Diseases; Demyelinations; Discipline; Disease; Disease Progression; Etiology; Experimental Autoimmune Encephalomyelitis; Foundations; Frequencies; Gene Expression; Gene Expression Profile; Genetic; Goals; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Instruction; Lead; Lesion; Libraries; Lysophosphatidylcholines; Mediating; Medical; Modeling; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nerve; Neuraxis; Neurons; Oligodendroglia; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pluripotent Stem Cells; Population; Preclinical Drug Evaluation; Process; Production; Progressive Disease; Property; Rattus; Recording of previous events; Relapse; Research; Rodent; Safety; Signal Transduction; Site; Slice; Solid; Source; Spinal Cord; Stem cells; System; Technology; Testing; Therapeutic; United States National Institutes of Health; Validation; cell type; clinical application; cost; cost effective; disability; disabling disease; drug efficacy; drug mechanism; drug testing; functional restoration; high throughput screening; improved; improved functioning; in vitro Assay; in vivo; in vivo Model; interest; mortality; mouse model; myelination; novel; novel therapeutics; pre-clinical; programs; public health relevance; relating to nervous system; remyelination; repaired; research clinical testing; response; screening; skills; stem cell differentiation; stem cell technology; success

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex, debilitating neural disorder associated with significant morbidity and mortality. Disease etiology is a result o unknown environmental and genetic factors, while disease pathology presents as inflammatory injury to the central nervous system (CNS) causing physical incapacity. This damage is a result of autoimmune-mediated destruction of oligodendrocytes causing demyelination. Prolonged demyelination leads to axonal damage occurring either in focal lesion sites and/or widespread throughout the CNS, depending on presentation of the disease. MS is treated with disease-modifying agents that target the immune system in an attempt to reduce the frequency of relapses and delay disease progression. These drugs have had limited success in improving patient outcomes and lack the unmet need to promote immediate remyelination. Identifying drugs that induce resident oligodendrocyte progenitor cell (OPC) mediated remyelination would provide patients a vital mechanism to halt disease progression and improve function. We propose to screen drugs that promote remyelination for repurposing in MS. To achieve this goal we have developed a proposal that incorporates the skill and expertise of multiple disciplines through a proven validation pipeline to interrogate drug entities that promote remyelination. We will begin with drugs that have a history of use in human clinical trials and assess their ability o promote rodent OPC maturation and myelin gene expression in our novel high throughput in vitro system. This system takes advantage of our technology to generate scalable sources of functional OPCs from pluripotent stem cells. Validated drug hits from our high throughput in vitro screen will then be tested in a tractable and economical ex vivo myelination assay utilizing organotypic rodent brain slice cultures. Moving forward, we will take our 5 most promising drug hits (as determined from in vitro and ex vivo assays) and test them in animal model systems regularly used to interrogate applicability to MS (lysolecithin-mediated spinal cord demyelination and Experimental Autoimmune Encephalomyelitis). Top drug hits will also be tested on human OPCs. Using our strengths in preclinical MS research and stem cell differentiation, we aim to identify efficacious pharmacological agents that promote remyelination by the end of this two year project. We are prepared to progress lead drugs identified from our studies to human clinical trials.

描述（由申请人提供）：多发性硬化症（MS）是一种复杂的、使人衰弱的神经疾病，与显着的发病率和死亡率相关。疾病病因是未知环境和遗传因素的结果，而疾病病理表现为中枢神经系统（CNS）炎症损伤，导致身体丧失能力。这种损伤是自身免疫介导的少突胶质细胞破坏导致脱髓鞘的结果。长期脱髓鞘导致轴突损伤发生在局灶性病变部位和/或广泛分布于整个中枢神经系统，具体取决于疾病的表现。多发性硬化症采用针对免疫系统的疾病缓解药物进行治疗，试图减少复发频率并延缓疾病进展。这些药物在改善患者预后方面取得的成功有限，并且缺乏促进立即髓鞘再生的未满足的需求。鉴定诱导常驻少突胶质细胞祖细胞（OPC）介导的髓鞘再生的药物将为患者提供阻止疾病进展和改善功能的重要机制。我们建议筛选促进髓鞘再生的药物，以便在多发性硬化症中重新利用。为了实现这一目标，我们制定了一项提案，通过经过验证的验证管道整合多个学科的技能和专业知识，以询问促进髓鞘再生的药物实体。我们将从具有人类临床试验使用历史的药物开始，评估它们在我们的新型高通量体外系统中促进啮齿动物 OPC 成熟和髓磷脂基因表达的能力。该系统利用我们的技术从多能干细胞中生成可扩展的功能性 OPC 来源。然后，我们将利用器官型啮齿动物脑切片培养物，在易于处理且经济的离体髓鞘形成测定中，对我们的高通量体外筛选中经过验证的药物进行测试。展望未来，我们将采用 5 种最有希望的药物（根据体外和离体测定确定），并在动物模型系统中对其进行测试，这些系统经常用于询问 MS（溶血卵磷脂介导的脊髓脱髓鞘和实验性自身免疫性脑脊髓炎）的适用性。热门药物也将在人类原花青素 (OPC) 上进行测试。利用我们在临床前多发性硬化症研究和干细胞分化方面的优势，我们的目标是在这个为期两年的项目结束时确定促进髓鞘再生的有效药物。我们准备将我们研究中发现的先导药物推进到人体临床试验中。