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

描述（由申请人提供）：多发性硬化症（MS）的发病机制有三个主要机制：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)神经再生抑制剂的积累。目前的多发性硬化症药物主要针对炎症，因此仅部分有效。同时针对这三种机制的治疗策略是非常可取的。神经干细胞（NSCs）可以通过细胞补充和适度的抗炎作用促进多发性硬化症动物模型——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，在全身移植时，NSCs完全迁移到发炎的中枢神经系统病灶，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，经过改造的NSCs可以产生三种治疗分子的混合物，针对MS的所有三种主要发病机制，这将是EAE/MS治疗的一种新颖而高效的方法。为了验证这一假设，我们将设计骨髓(BM)-NSCs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；和LINGO-1- fc，一种可溶解的LINGO-1拮抗剂，可阻断神经再生抑制剂。它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中的作用机制将在三个特定的目标中进行测试。该方法的其他优点包括：NSCs具有髓鞘再生和神经细胞再生的内在特性；BM- nscs的现成可用性和自体能力（来自患者自身的BM），以及Tet-on系统对转导基因的可控表达。我们相信，针对MS/EAE的所有三种主要机制设计的BM-NSCs将为一种新的、易于获得的、自体的、高效的MS治疗铺平道路。

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.