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

一种用于治疗 1 型糖尿病的新型免疫定向益生菌

基本信息

批准号：
10653229
负责人：
Gary Fanger
金额：
$ 98.36万
依托单位：
RISE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653229
关键词：
Affect Animals Antigens Autoimmune Diseases Bacteria Beta Cell Biological Response Modifier Therapy Blindness Blood Cell Line Cells Chronic Clinic Clinical Clinical Research Clinical Trials Consent Data Dendritic Cells Diabetes Mellitus Diagnosis Disease Documentation Dose Drug Exposure Drug Kinetics Drug usage Ensure Environment Enzyme-Linked Immunosorbent Assay Equilibrium Excipients Feces Food Formulation Genetic Goals Human Immune Immunity Immunologics Inbred NOD Mice Incidence Inflammatory Infrastructure Insulin Insulin-Dependent Diabetes Mellitus Intestinal permeability Intestines Kidney Failure Lactococcus lactis Leaky Gut Life Ligands Local Therapy Measures Mediating Medical Monitor Mucous Membrane Oral Organism Pathogenicity Patients Pharmaceutical Preparations Phase Positioning Attribute Prediction of Response to Therapy Prevalence Probiotics Process Production Quality of life Regulatory T-Lymphocyte Residual state Risk Running Safety Serum Social Interaction Stroke Structure of beta Cell of islet T-Lymphocyte Therapeutic Treatment outcome Up-Regulation Well in self Work autoimmune pathogenesis autoreactive T cell biomarker identification cell type colonization factor antigens commensal microbes commercialization cost curative treatments cytokine design drug mechanism effector T cell experimental study fecal microbiome first-in-human gastrointestinal epithelium glycemic control gut microbiome gut microbiota immunoregulation in vivo insulin dependent diabetes mellitus onset islet manufacture microbiome novel novel strategies pathogen pharmacologic phase 1 study pre-Investigational New Drug meeting pre-clinical probiotic therapy product development receptor research clinical testing side effect targeted delivery targeted treatment

项目摘要

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.

项目概要我们的目标是开发一种新型的、免疫导向的、基于乳酸乳球菌益生菌的治疗方法 1 型糖尿病 (T1D)1 T1D 是一种毁灭性的疾病，没有治愈方法，胰岛素是唯一的治疗方法。唯一可用的 T1D 药物不仅影响血糖控制，还影响患者生活的许多重要方面，包括情绪健康、生活质量、工作能力和社交互动25。导致失明、肾衰竭、中风和其他自身免疫性疾病的风险增加。因此，迫切需要针对 T1D 制定新的前沿策略。 T1D 发病率和患病率的急剧上升不能仅用遗传因素来解释暗示环境，特别是肠道微生物组，是疾病发病机制的罪魁祸首62。肠道微生物群影响包括免疫在内的多种宿主功能，1型糖尿病患者呈现出变化此外，与免疫失调和肠道渗漏相关的肠道微生物群6。微生物组疗法（FMT）作为一般治疗方法充满了困难，包括可能的转移对照临床研究表明，FMT 可以阻止新发 T1D63 的进展。一种有前途且可能安全的 T1D 治疗方法，它利用人体自身的自然机制微生物组相关的免疫调节机制是利用口服、肠道局部和靶向治疗控制共生微生物与肠道上皮层内衬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 是一种免疫定向益生菌，由食品级乳酸乳球菌 (L.) 菌株组成表达定植因子抗原 I (CFA/I) 是一种活生物治疗产品，代表将益生菌的安全性与靶向治疗相结合，是治疗 T1D 的突破性新方法 R-2487 的功能已被证明可以通过 R-2487 发挥作用来减少 T1D。将 CFA/I 靶向递送至肠道，与粘膜树突状细胞结合以驱动全身调节性 T 细胞 (Treg) 的上调 Treg 的诱导重置了促炎性 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，从而导致旁观者由于自身免疫性疾病（包括 T1D）的异质性发病机制带来了许多挑战。对于针对特定抗原进行耐受或单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更广泛、更有效的疾病纠正机制。该申请旨在完成 R-2487 IND 启用研究并向 FDA 提交 IND 密钥。该提案的目标是：1) 最终确定 R-2487 的体内表征；2) 药物的 GMP 生产；物质和药品；3) 提交 IND 申请以评估近期发病的 T1D 患者的活性。 R-2487的成功商业化将为治疗T1D带来深远的医学进步。