A Novel Immunological-Directed Synthetic Biology-Based Drug for the Treatment of Multiple Sclerosis

项目摘要 我们的目标是开发一种新的，免疫导向的合成生物学为基础的治疗， 多发性硬化症（MS）。MS是一种破坏性的疾病，其特征是免疫反应加剧， 髓磷脂这种疾病会影响患者生活的许多重要方面，包括情感健康，质量 生活、工作能力和社会交往的能力。此外，MS患者存在增加的严重 继发性并发症，包括失明、肾衰竭、中风和其他自身免疫性疾病。 因此，迫切需要开发新的尖端策略来治疗MS。 肠-脑轴被认为是连接中枢神经系统和中枢神经系统的双向通讯系统。 gut13，现在涉及疾病的发病机制。MS患者存在生态失调的肠道微生物组 缺乏调节性T细胞（T细胞）15，16，18，19。益生菌的消费量显示， 通过增加抗炎性细胞因子和Tregs 17来降低疾病的严重程度，证实了 肠脑轴治疗MS的一种有希望的方法是利用人体自身的天然微生物组- 与口服、肠道局部和靶向治疗相关的免疫调节机制，以控制宿主 免疫细胞衬肠上皮层，以指导重建系统性免疫稳态。 R-2487是由食品级乳球菌（Lactococcus（L.） 表达定殖因子抗原I（CFA/I）的乳酸菌菌株。R-2487是一种活性生物素产品， 代表了一种新的突破性的方法，通过结合益生菌的安全性， CFA/I配体的靶向功能。R-2487已被证明可以减少MS样症状， animals动物21，22. R-2487通过将CFA/I靶向递送至肠道并与粘膜结合而发挥作用。 树突状细胞来驱动TcB的系统性上调。Tendon的引入重新设定了平衡， 促炎性T效应细胞减少导致自身免疫性疾病的炎症过程， 导致旁观者的容忍。由于包括MS在内的自身免疫性疾病的发病机制不同， 对靶向用于耐受化的特异性抗原或单细胞类型的疗法提出了许多挑战， 细胞因子，R-2487介导的旁观者耐受诱导提供了更广泛和更有效的机制， 疾病矫正 本申请旨在完成R-2487 IND使能研究，以支持启动首次人体试验 这项重要的新疗法的MS试验。该提案的主要目的是：1）完成体内表征， R-2487，确定临床试验中使用的起始临床剂量和重要生物标志物; 2） 生产临床GMP原料药和制剂;以及3）完成IND使能GLP 毒理学研究R-2487的成功商业化将为人类提供深刻的医学进步。 治疗MS。

Project Summary Our goal is to develop a novel, immunological-directed synthetic biology-based therapeutic for the treatment of Multiple Sclerosis (MS). MS is a devastating characterized by an exacerbated immune response that destroy myelin. This disease affects many important aspects of a patient's life, including emotional well-being, quality of life, working ability, and social interactions. In addition, MS patients present increased risk of severe secondary complications, including blindness, kidney failure, stroke, and additional autoimmune disorders. Therefore, there is an urgent need to develop new cutting-edge strategies to treat MS. The gut–brain axis has been recognized as a bi-directional communication system connecting the CNS to the gut13 that is now implicated in the disease etiopathogenesis. MS patients present a dysbiotic gut microbiome with a deficiency in regulatory T cells (Tregs)15, 16, 18, 19. Probiotic consumption showed an improvement in the disease severity by increasing anti-inflammatory cytokines and Tregs17, corroborating the important role of the gut-brain axis. A promising approach for the treatment of MS is to leverage the body’s own natural microbiome- associated immune regulatory mechanisms with oral, gut localized and targeted therapy to control host immune cells lining the gut epithelial layer to direct reestablishment of systemic immune homeostasis. R-2487 is an immunologically-directed recombinant probiotic consisting of the food-grade, Lactococcus (L.) lactis strain expressing Colonization Factor Antigen I (CFA/I). R-2487 is a live biotherapeutic product that represents a novel breakthrough approach for the treatment of MS by combining the safety of a probiotic with the targeted functionality of the CFA/I ligand. R-2487 has been showed to diminish MS-like symptoms in animals21, 22. R-2487 works via targeted delivery of CFA/I to the intestinal tract where it engages mucosal dendritic cells to drive systemic upregulation of Tregs. The induction of Tregs resets the balance with proinflammatory T effector cells to reduce inflammatory processes that contribute to autoimmune disease, leading to bystander tolerance. Since heterogeneous pathogenesis of autoimmune disease, including MS, poses many challenges for therapies that target specific antigens for tolerization or a single cell type or cytokine, R-2487-mediated bystander tolerance induction offers a broader and more impactful mechanism of disease correction. This application is designed to complete R-2487 IND enabling studies to support initiation of a first-in-human MS trial for this important new therapy. The key aims of this proposal are: 1) finalize in vivo characterization of R-2487, identifying starting clinical dose and important biomarkers to be used in the clinical trial; 2) manufacture of clinical GMP drug substance and drug product; and 3) complete the IND-enabling GLP toxicology study. Successful commercialization of R-2487 will provide a profound medical advancement for treating MS.