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、免疫导向的乳酸乳杆菌益生菌为基础的治疗方法。 1型糖尿病(T1D)1.T1D是一种毁灭性的疾病，目前还没有根治方法，使用胰岛素治疗 唯一可用的药物。T1D不仅影响血糖控制，还影响患者生活的许多重要方面， 包括情感幸福感、生活质量、工作能力和社会互动25。此外，T1D患者 罹患失明、肾功能衰竭、中风和其他自身免疫性疾病的风险增加。 因此，迫切需要为T1D开发新的前沿战略。 T1D发病率和患病率的急剧上升不能仅仅用遗传因素来解释 暗示环境，特别是肠道微生物群，是疾病病因62的罪魁祸首。 肠道微生物群影响包括免疫在内的多种宿主功能，T1D患者会出现变化 肠道微生物区系中与免疫松弛和肠道渗漏有关6。此外，虽然粪便 微生物组治疗(FMT)作为一种普遍的治疗方法充满了困难，包括可能的转移 病原体，对照临床研究表明，FMT阻止了新发病的T1D63的进展。 一种有希望且潜在安全的治疗T1D的方法，它利用人体自身的自然 微生物组相关免疫调节机制是利用口服、肠道局部和靶向治疗 控制肠道上皮层内共生微生物和宿主免疫细胞之间的特定相互作用 表达关键的免疫调节受体。 R-2487是一种免疫导向益生菌，由食品级乳球菌(L.)乳酸菌菌株 表达克隆因子抗原I(CFA/I)。R-2487是一种活的生物治疗产品，代表着 益生菌安全性与靶向联合治疗T1D的突破性新方法 CFA/I配体的官能度。R-2487已被证明可以减少动物的T1D。R-2487通过 CFA/I靶向肠道与粘膜树突状细胞结合驱动全身 上调调节性T细胞(Tregs)。Tregs的诱导重置了促炎T细胞的平衡 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 宽容。由于包括T1D在内的自身免疫性疾病的不同发病机制构成了许多挑战 对于靶向耐受的特定抗原或单一细胞类型或细胞因子的治疗，R-2487介导 旁观者耐受诱导提供了一种更广泛和更有效的疾病纠正机制。 此应用程序旨在完成R-2487 IND启用研究并向FDA提交IND。钥匙 这项建议的目的是：1)最终确定R-2487的体内特性；2)药物的GMP制造 3)提交IND申请，以评估新发的T1D患者的活性。 R-2487的成功商业化将为治疗T1D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.