A Novel Immunologically Directed Probiotic for the Treatment of Type 1 Diabetes

项目摘要 我们的目标是开发一种新型的、免疫导向的L。基于乳酸菌益生菌的治疗剂， 1型糖尿病（T1 D）T1 D是一种毁灭性的疾病，没有治愈性的治疗方法， 唯一可用的药物。T1 D不仅影响血糖控制，还影响患者生活的许多重要方面， 包括情绪健康、生活质量、工作能力和社会交往25。此外，T1 D患者 存在发展成失明、肾衰竭、中风和其他自身免疫性疾病的风险增加。 因此，迫切需要为T1 D制定新的尖端战略。 T1 D发病率和患病率的急剧上升不能仅由遗传因素解释 暗示环境，特别是肠道微生物组，是疾病病因的罪魁祸首62。 肠道微生物组影响多种宿主功能，包括免疫力，T1 D患者出现变化 在与免疫失调和肠道渗漏相关的肠道微生物群中6.此外，虽然粪便 微生物组疗法（FMT）作为一般治疗充满了困难，包括可能的微生物组转移。 针对病原体，对照临床研究证明FMT阻止新发T1 D 63的进展。 一种有前途的和潜在的安全的方法来治疗T1 D，利用人体自身的自然 微生物组相关的免疫调节机制是使用口服，肠道局部和靶向治疗， 控制肠道微生物和肠道上皮层内的宿主免疫细胞之间的特异性相互作用 表达关键的免疫调节受体。 R-2487是由食品级乳球菌（Lactococcus（L.）乳酸亚种菌株 表达定殖因子抗原I（CFA/I）。R-2487是一种活性生物素产品， 通过将益生菌的安全性与靶向药物结合， CFA/I配体的功能性。R-2487已被证明可以减少动物中的T1 D 9。R-2487通过以下方式工作： 将CFA/I靶向递送至肠道，在肠道中其与粘膜树突状细胞接合以驱动全身性免疫应答。 上调调节性T细胞（TcB）。诱导T淋巴细胞重新平衡与促炎性T淋巴细胞 效应细胞减少炎症过程，导致自身免疫性疾病，导致旁观者 宽容由于包括T1 D在内的自身免疫性疾病的异质性发病机制提出了许多挑战， 对于靶向耐受化的特异性抗原或单细胞类型或细胞因子的疗法，R-2487介导的 旁观者耐受诱导提供了更广泛和更有效的疾病纠正机制。 本申请旨在完成R-2487 IND使能研究并向FDA提交IND。关键 该提案的目的是：1）完成R-2487的体内表征; 2）药物的GMP生产 物质和药物产品;和3）提交IND申请以评估在新近发作的T1 D患者中的活性。 R-2487的成功商业化将为治疗T1 D提供深刻的医学进步。

Project Summary Our goal is to develop a novel, immunologically-directed L. lactis probiotic-based therapeutic for the treatment of Type 1 Diabetes (T1D)1. T1D is a devastating disease and there is no curative treatment, with insulin the only drug available. T1D affects not only glycemic control but also many important aspects of a patient's life, including emotional well-being, quality of life, working ability, and social interactions25. In addition, T1D patients present increased risk of developing blindness, kidney failure, stroke, and additional autoimmune disorders. Therefore, there is an urgent need to develop new cutting-edge strategies for T1D. The steep rise in the incidence and prevalence of T1D cannot be explained solely by genetic factors implicating the environment, and specifically the gut microbiome, as culprit for the disease etiopathogenesis62. The gut microbiome influences multiple host functions, including immunity, and T1D patients present changes in gut microbiota associated with immunological deregulation and gut leakiness6. Moreover, while fecal microbiome therapy (FMT) is fraught with difficulties as a general treatment including possible transfer of pathogenic organisms, controlled clinical studies demonstrate that FMT halts the progress of new onset T1D63. A promising and potentially safe approach to the treatment of T1D that leverages the body’s own natural microbiome-associated immune regulatory mechanisms is to use oral, gut localized and targeted therapy to control specific interactions between commensal microbes and host immune cells lining the gut epithelial layer that express key immunoregulatory receptors. R-2487 is an immunologically-directed 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 T1D by combining the safety of a probiotic with the targeted functionality of the CFA/I ligand. R-2487 has been showed to diminish T1D in animals9. R-2487 works via targeted delivery of CFA/I to the intestinal tract where it engages mucosal dendritic cells to drive systemic upregulation of regulatory T cells (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 T1D, 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 and file an IND with the FDA. The key aims of this proposal are: 1) finalize in vivo characterization of R-2487; 2) GMP manufacturing of drug substance and drug product; and 3) submit IND application to evaluate activity in recent onset T1D patients. Successful commercialization of R-2487 will provide a profound medical advancement for treating T1D.