A Novel Immunological Probiotic for Treating Inflammatory Bowel Disease

一种治疗炎症性肠病的新型免疫益生菌

• 批准号: 10380146
• 负责人: Gary Fanger
• 金额: $ 45.9万
• 依托单位: RISE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380146
• 关键词: Adult; Animal Model; Animals; Bacteria; Binding; Biological; Biological Assay; Biological Markers; Biomass; C Type Lectin Receptors; C-Type Lectins; CD209 gene; Cell Adhesion Molecules; Cells; Chemicals; Climacteric; Clinical; Clinical Research; Clinical Trials; Colitis; Crohn' s disease; Data; Dendritic Cells; Development; Diagnosis; Digestive System Disorders; Disease; Dose; Engineering; Environment; Environmental Risk Factor; Experimental Models; Food; Future; Genetic Engineering; Goals; Growth; Gut Mucosa; Homologous Gene; Human; Human Microbiome; Immune; Immune system; Immunity; Immunologics; Industry; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Investments; Lactobacillus; Lactococcus; Life; Ligands; Maintenance; Mediating; Medical; Membrane; Methods; Mucous Membrane; Mus; Nutrient; Oral; Patients; Pattern recognition receptor; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Play; Population; Preparation; Probiotics; Process; Property; Proteins; Recombinants; Regulatory T-Lymphocyte; Research; Research Design; Role; Signal Transduction; Small Business Innovation Research Grant; Stomach; Surface; Symptoms; Therapeutic; Thymidine; Toxicology; Ulcerative Colitis; base; biomarker identification; cell bank; chronic inflammatory disease; commensal bacteria; commercialization; cost; cytokine; delivery vehicle; design; dosage; drug development; gastrointestinal; genetic manipulation; gut homeostasis; gut inflammation; gut microbiome; host microbiota; immune health; improved; innovation; interest; intestinal barrier; intestinal epithelium; lactic acid bacteria; lipoteichoic acid; manufacturing scale-up; microbiome; microbiota; murine colitis; normal microbiota; novel; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; prevent; probiotic therapy; receptor; research clinical testing; scale up; side effect; success; vaccine delivery

Project Summary The goal of this project is to develop a novel immunologically designed probiotic therapy to inhibit gut inflammatory processes for the treatment of inflammatory bowel disease (IBD). Over 3 million adults in the U.S. suffer from IBD, an umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tract: Crohn’s disease (CD) and ulcerative colitis (UC)6. IBD is typically diagnosed in the second or third decades of life; it is life-long, and there is no cure. Current IBD treatments are systemic and can have serious side-effects. Novel therapies that are safe and effective, particularly restoring the natural interaction between the immune system and gut microbiome, are needed and would be life-changing for patients. Intestinal immune regulatory signals tightly govern healthy gut homeostasis, and their breakdown may result in IBD38. The human microbiome, harboring trillions of bacteria, is a critical regulator of these mechanisms. Commensal bacteria function to maintain intestinal epithelial barrier integrity and regulate innate and adaptive immune cell function39. Lactobacillus (L.) acidophilus, a common bacterial species sold as a probiotic that ‘promotes immune health’, contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA)40-43. These Slps interact with pattern recognition receptors (PRR; e.g., C-type lectin receptors) expressed on innate intestinal cells to fine-tune immunity in steady state and disease conditions42. Recently, our research team demonstrated that SlpA binding to the C-type lectin Specific Intracellular adhesion molecule-3 Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells lining the gut prevents experimentally induced colitis in multiple models3. Oral delivery of SlpA reduced inflammatory cytokines, strengthened the mucosal membrane barrier, and supported a healthier microbiota make-up in animal models of gut inflammation. In contrast, the effects and protection were not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3 plays a key protective role in regulating the disease condition3. Our goal is to develop R-3750, a SlpA-expressing, thymidine-dependent L. lactis strain, as a novel, orally administered probiotic that functions in IBD to reduce gut inflammation, improve gastrointestinal mucosal barrier function, and restore the natural microbiome make-up. L. lactis provides two key advantages as a delivery vehicle for conveying SlpA to the gut; namely, it has already been safely used in human clinical trials in a genetically manipulated form1, 4 and it does not express any native Slps but can be engineered to selectively overexpress SlpA. This Phase II SBIR application is intended to build upon success of the Phase I and advance R-3750 towards clinical testing. The specific Aims are: 1) optimize R-3750 upstream process development to support manufacturing, 2) create GMP master cell bank, 3) manufacture R-3750 for animal dosing/biomarker and GLP toxicology studies, and 4) complete R-3750 dose optimization and biomarker- based PD studies in mice.

项目摘要 该项目的目的是开发一种新型的免疫学设计的益生菌疗法来抑制肠道 治疗炎症性肠病（IBD）的炎症过程。美国超过300万成年人 遭受IBD的困扰，雨伞术语包括两种胃肠道的慢性炎症性疾病 道：克罗恩病（CD）和溃疡性结肠炎（UC）6。 IBD通常在第二或第三次诊断 数十年的生活；它是终身，无法治愈。当前的IBD治疗是全身性的，可以很严重 副作用。安全有效的新型疗法，尤其是恢复自然相互作用 免疫系统和肠道微生物组是需要的，并且会改变患者的生活。 肠道免疫调节信号严格控制健康的肠稳态，它们的崩溃可能导致 IBD38。人类微生物组含有数万亿个细菌，是这些机制的关键调节剂。 共生细菌的功能可维持肠上皮屏障完整性并调节先天和适应性 免疫细胞功能39。乳杆菌（L.）嗜酸菌，一种常见的细菌，作为益生菌出售， “促进免疫健康”包含独特的表面层蛋白（SLP），包括SLPA，SLPB，SLPX和 Lipoteichoic Acid（LTA）40-43。这些SLP与模式识别受体相互作用（PRR;例如C型讲座 受体）在先天肠细胞上表达以在稳态和疾病条件下微调免疫史42。 最近，我们的研究小组表明，SLPA与C型凝集素特异性细胞内粘附结合 分子-3抓住非整合素同源物相关的3（SIGNR3）受体，在树突状细胞衬里表达 肠道可防止多种模型中实验诱导的结肠炎3。 SLPA的口服递送减少了炎症 细胞因子增强粘膜膜屏障，并支持更健康的菌群化妆 肠道注射的动物模型。相反，在signr3 - / - 小鼠中未观察到效果和保护， 表明SLPA与SIGNR3相互作用在调节疾病状况中起关键的保护作用3。 我们的目标是开发R-3750，这是一种表达SLPA的胸苷依赖性乳酸乳杆菌菌株，作为一种小说，口服 给予IBD功能可减少肠道注射，改善胃肠粘膜的益生菌 屏障功能，并恢复天然微生物组的化妆。 Lactis Lactis提供了两个关键优势 将SLPA运送到肠道的输送工具；也就是说，它已经在人类临床试验中安全地使用 在一般操纵的Form1、4中，它不表达任何本地SLP，但可以设计为 有选择地表达SLPA。此II阶段SBIR应用程序旨在建立在第一阶段的成功基础上 并将R-3750推进临床测试。具体目的是：1）优化R-3750上游过程 支持制造业的开发，2）创建GMP大型细胞库，3）为动物制造R-3750 剂量/生物标志物和GLP毒理学研究，以及4）完整的R-3750剂量优化和生物标志物 基于小鼠的PD研究。