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NSCs produce a triply effective cocktail in the CNS for MS/EAE therapy

NSC 在 CNS 中产生三重有效的鸡尾酒，用于 MS/EAE 治疗

基本信息

批准号：
8545912
负责人：
GUANG-XIAN ZHANG
金额：
$ 29.45万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545912
关键词：
Adult Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Astrocytes Autologous B-Lymphocytes Bone Marrow Bone Marrow Cells Brain Brain-Derived Neurotrophic Factor Cells Chronic Clinical Complex Demyelinations Dendritic Cells Disease Disease Progression Effectiveness Engineering Experimental Autoimmune Encephalomyelitis Failure Genes Granulocyte-Macrophage Colony-Stimulating Factor Growth Immunity In Situ Inflammation Inflammatory Inflammatory Infiltrate Interferons Interleukin-10 Interleukin-17 Interleukin-4 Mediating Microglia Multiple Sclerosis Myelin Myelin Associated Glycoprotein Neuraxis Neuroglia Neuronal Dysfunction Neurons Neurotrophin 3 Oligodendroglia Pathogenesis Patients Peripheral Pharmaceutical Preparations Population Production Property Reagent Recovery of Function Recurrent disease Relapse Solid Staging System Testing Tetanus Helper Peptide Therapeutic Therapeutic Effect Transplantation autoreactive T cell cellular engineering central nervous system demyelinating disorder cytokine effective therapy fetal human RTN4 protein immunoregulation in vivo inhibitor/antagonist interleukin-23 macrophage myelination nerve stem cell neuron loss neurotrophic factor novel novel strategies oligodendrocyte precursor oligodendrocyte-myelin glycoprotein receptor relating to nervous system remyelination repaired stem cell therapy subventricular zone therapeutic effectiveness tool tumor

项目摘要

DESCRIPTION (provided by applicant): Three major mechanisms contribute to the pathogenesis of multiple sclerosis (MS): 1) persistent central nervous system (CNS) multifocal inflammation; 2) demyelination and neuron loss; and 3) accumulation of inhibitors of neuroregeneration. Current MS medications target mainly inflammation, and are thus only partially effective. A therapeutic strategy that targets all three mechanisms simultaneously is highly desirable. Neural stem cells (NSCs) can promote multifocal remyelination and functional recovery in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by cell replenishment and a modest anti-inflammatory effect. Furthermore, NSCs migrate exclusively into inflamed CNS foci upon systemic transplantation, making them a unique tool for delivering therapeutic molecules in situ. Our central hypothesis is that NSCs engineered to produce a cocktail of three therapeutic molecules that target all three main mechanisms of MS pathogenesis will be a novel and highly effective approach in EAE/MS therapy. To test this hypothesis, we will engineer bone marrow (BM)-NSCs to produce IL-10, a potent anti-inflammatory cytokine; NT-3, a potent neurotrophic factor for myelination and neuron survival; and LINGO-1-Fc, a soluble LINGO-1 antagonist that blocks neuroregeneration inhibitors. Their therapeutic effect in chronic and relapsing-remitting EAE and the mechanisms of action in immunomodulation and neural protection will be tested in three specific aims. Additional advantages of this approach include: the intrinsic properties of NSCs for remyelination and neural cell re-population; the ready availability and autologous capacity of BM-NSCs (from patients' own BM), and controllable expression of transduced genes by the Tet-on system. We believe that BM-NSCs engineered to target all three major mechanisms of MS/EAE should pave the way to a novel, easily accessible, autologous, and highly effective MS therapy.

描述(申请人提供)：多发性硬化症(MS)的三种主要发病机制：1)持续性中枢神经系统(CNS)多灶性炎症；2)脱髓鞘和神经元丢失；以及3)神经再生抑制物积累。目前的多发性硬化症药物主要针对炎症，因此只有部分有效。同时针对所有这三种机制的治疗策略是非常可取的。神经干细胞(NSCs)可通过细胞补充和温和的抗炎作用，促进实验性自身免疫性脑脊髓炎(EAE)的多灶性再髓鞘形成和功能恢复。此外，神经干细胞在系统移植后仅迁移到发炎的中枢神经系统灶中，使其成为原位运送治疗分子的独特工具。我们的中心假设是，神经干细胞被设计成产生三种治疗分子的鸡尾酒，这些分子针对MS发病的所有三个主要机制，将是治疗EAE/MS的一种新的、高效的方法。为了验证这一假设，我们将设计骨髓(BM)-神经干细胞产生IL-10，一种有效的抗炎细胞因子；NT-3，一种有效的髓鞘形成和神经元存活的神经营养因子；以及LINGO-1-Fc，一种可溶的LINGO-1拮抗剂，阻断神经再生抑制物。它们对慢性和复发缓解型EAE的治疗效果以及在免疫调节和神经保护方面的作用机制将在三个特定目标下进行测试。这种方法的其他优点包括：神经干细胞用于髓鞘再分化和神经细胞重新分化的固有特性；骨髓-神经干细胞(来自患者自己的骨髓)的现成可获得性和自体能力，以及通过Tet-on系统可控制的转导基因的表达。我们相信，针对MS/EAE的所有三种主要机制而设计的BM-NSCs应该为一种新的、容易获得的、自体的和高效的MS治疗铺平道路。