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

• 批准号: 8661315
• 负责人: GUANG-XIAN ZHANG
• 金额: $ 30.21万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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/8661315
• 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; Nerve Regeneration; 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

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（由申请人提供）：多发性硬化（MS）的发病机制有三种主要机制：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; 3）神经再生抑制剂蓄积。目前的MS药物主要针对炎症，因此仅部分有效。同时靶向所有三种机制的治疗策略是高度期望的。 神经干细胞（NSCs）可以通过细胞补充和适度的抗炎作用促进实验性自身免疫性脑脊髓炎（EAE）的多灶性髓鞘再生和功能恢复。此外，NSC在全身移植后仅迁移到发炎的CNS病灶中，使其成为原位递送治疗分子的独特工具。 我们的中心假设是，神经干细胞工程，以产生一个鸡尾酒的三种治疗分子，目标的MS发病机制的所有三个主要机制，将是一种新的和高度有效的方法在EAE/MS治疗。为了验证这一假设，我们将设计骨髓（BM）-NSC以产生IL-10，一种有效的抗炎细胞因子; NT-3，一种用于髓鞘形成和神经元存活的有效神经营养因子;和LINGO-1-Fc，一种可阻断神经再生抑制剂的可溶性LINGO-1拮抗剂。他们在慢性和复发缓解型EAE中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中进行测试。这种方法的其他优点包括：用于髓鞘再生和神经细胞再增殖的NSC的固有特性; BM-NSC的现成可用性和自体能力（来自患者自己的BM），以及Tet-on系统对转导基因的可控表达。 我们认为，针对MS/EAE的所有三种主要机制设计的BM-NSC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。