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、以免疫学为导向的、以合成生物学为基础的治疗方法 多发性硬化(MS)。多发性硬化症是一种毁灭性的疾病，其特征是免疫反应加剧 髓鞘。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。此外，多发性硬化症患者出现严重的 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多发性硬化。 肠-脑轴被认为是连接CNS和 Gut13，它现在被认为与疾病的病因有关。多发性硬化症患者呈现肠道微生物群失调 缺乏调节性T细胞(Treg)15、16、18、19。益生菌的消费显示出 通过增加抗炎细胞因子和Tregs17来加重疾病严重程度，证实了 肠轴-脑轴。治疗多发性硬化症的一种有希望的方法是利用人体自身的自然微生物群-- 口服、肠道定位和靶向治疗控制宿主的相关免疫调节机制 免疫细胞排列在肠道上皮层，直接重建全身免疫平衡。 R-2487是一种免疫导向的重组益生菌，由食品级乳球菌(L.) 表达定居因子抗原I(CFA/I)的乳酸菌。R-2487是一种活的生物治疗产品， 代表了一种治疗多发性硬化症的新的突破性方法，将益生菌的安全性与 CFA/I配体的靶向功能。R-2487已被证明可以减轻 动物21，22。R-2487通过将CFA/I靶向输送到与粘膜接触的肠道发挥作用 树突状细胞驱动Tregs的系统上调。Tregs的诱导重置了平衡 前炎性T效应细胞，以减少导致自身免疫性疾病的炎症过程， 导致对旁观者的容忍。由于自身免疫性疾病的异质性发病机制，包括多发性硬化症， 针对特定抗原的耐受性或单一细胞类型的治疗提出了许多挑战 细胞因子R-2487介导的旁观者耐受诱导提供了一种更广泛和更有效的机制 疾病矫正。 此应用程序旨在完成R-2487 IND，使研究能够支持人类第一次 多发性硬化症试验这一重要的新疗法。这项建议的主要目的是：1)最终确定在体内的特征 R-2487，确定临床起始剂量和临床试验中使用的重要生物标志物；2) 生产临床GMP药材和药品；3)完成IND-Enabling GLP 毒理学研究。R-2487的成功商业化将为 治疗多发性硬化症

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.