Therapeutics for inflammatory bowel disease from the microbiome

从微生物组治疗炎症性肠病

• 批准号: 9201532
• 负责人: Sarkis K Mazmanian
• 金额: $ 197.34万
• 依托单位: SYMBIOTIX BIOTHERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201532
• 关键词: Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antigens; Area; Asthma; Award; Bacteria; Bacteroides fragilis; Biological; Biological Products; Biological Response Modifier Therapy; Biology; Biopsy; Biotechnology; California; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Colitis; Collection; Complex; Contracts; Data; Dendritic Cells; Development; Disease; Disease Management; Doctor of Philosophy; Engineering; Etiology; Experimental Models; Foundations; Gastrointestinal Diseases; Goals; Grant; Human; Human Microbiome; Human body; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Institutes; Interleukin-10; Interleukin-17; Intestines; Investigational Drugs; Life; Ligands; Link; Manufactured Materials; Manufacturer Name; Mediating; Medical; Membrane; Microbe; Microbiology; Molecular Structure; Multiple Sclerosis; Mus; Oral; Oral Administration; Organism; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Polysaccharides; Population; Pre-Clinical Model; Process; Production; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Rheumatoid Arthritis; Role; Science; Serious Adverse Event; Signal Transduction; Small Business Technology Transfer Research; Staging; Steroids; Structure; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; TLR2 gene; Technology; Therapeutic; Therapeutic Agents; Therapeutic immunosuppression; Tissues; Toxicology; Translating; United States; Vesicle; Work; analytical method; base; clinical investigation; germ free condition; gut microbiome; human disease; manufacturing process; manufacturing scale-up; medical complication; medical schools; method development; microbial; microbiome; microbiota; microorganism; mouse model; next generation; novel; novel strategies; novel therapeutics; pre-clinical; prevent; professor; programs; protective effect; receptor; reduce symptoms; scale up; single molecule; translational study

PROJECT SUMMARY / ABSTRACT Interactions between the gut microbiome and the immune system have been linked to inflammatory bowel disease (IBD). IBD is a chronic and progressive gastrointestinal disease characterized by uncontrolled activation of the intestinal immune system resulting in severe medical complications, affecting over 1.5 million patients in the United States. It is a disease of high unmet medical need, currently treatable with only one of twelve approved immunosuppressive therapies, often leading to toxic side effects. Symbiotix Biotherapies, Inc. is an early-stage biotechnology company developing a first-in-class therapeutic agent for IBD and other immune-mediated diseases based on recent discoveries emerging from the human microbiome. Our scientific founders have identified a specific gut commensal organism, Bacteroides fragilis, that induces interleukin (IL)- 10-secreting regulatory T cells (Tregs) that are able to dampen the pro-inflammatory activities of Th1, Th2 and Th17 subsets of T cells. We have furthermore identified a specific capsular polysaccharide (PSA) from this organism responsible for the protective effect, shown that PSA works through a novel mechanism of Treg activation to expand anti-inflammatory T cell populations in mice, and shown that oral administration of purified PSA is protective in multiple models of mouse colitis. Our objective for this Phase 2 STTR project is to conduct key translational activities that will be essential for advancing PSA towards an IND filing as a safe and efficacious oral first-in-class treatment for human inflammatory bowel disease. The project consists of 3 Specific Aims: In Specific Aim 1, we will expand on initial human in vitro efficacy studies that demonstrate the capacity of PSA to convert naïve T cells into Treg cells in culture that secrete anti-inflammatory IL-10, to evaluate the effect of PSA on PBMCs and gut tissue taken from patients with inflammatory bowel disease. In Specific Aim 2, we will work with a biopharmaceutical contract manufacturer to scale up the manufacturing process that we have optimized to enable production of 200L batches that can support IND-enabling GLP toxicology studies. In Specific Aim 3, we will carry out analytical method development to support scaleup and production of larger quantities of material necessary for tox studies and clinical trials. These Specific Aims will lay the essential groundwork allowing PSA to move to IND filing and Phase I clinical trial. As our company works to translate the groundbreaking academic studies that have resulted in the first therapeutic molecule to emerge from the human microbiome, Phase 2 STTR support will advance this revolutionary treatment option for IBD to the brink of human clinical trials, and will pave the way for application of PSA to other immune- mediated diseases such as multiple sclerosis, asthma and rheumatoid arthritis.

项目总结/摘要 肠道微生物组和免疫系统之间的相互作用与炎症性肠病有关 疾病（IBD）。IBD是一种慢性进行性胃肠道疾病， 激活肠道免疫系统，导致严重的医疗并发症，影响超过150万人 美国的病人。这是一种高度未满足医疗需求的疾病，目前只有一种治疗方法， 12种批准的免疫抑制疗法，通常会导致毒副作用。Symbiotix Biotherapies，Inc. 是一家早期阶段的生物技术公司，开发一流的IBD和其他治疗药物， 免疫介导的疾病，基于最近发现的人类微生物组。我们的科学 创始人已经确定了一种特定的肠道微生物，脆弱拟杆菌，诱导白细胞介素（IL）- 10-分泌调节性T细胞（TCLs），其能够抑制Th 1、Th 2和Th 3的促炎活性， Th 17 T细胞亚群。我们还从该细胞中鉴定了一种特异性的荚膜多糖（PSA）。 负责保护作用的生物体，表明PSA通过Treg的新机制起作用 激活以扩增小鼠中的抗炎性T细胞群，并且显示口服施用纯化的 PSA在多种小鼠结肠炎模型中具有保护作用。我们第二阶段STTR项目的目标是 关键的翻译活动，这对于推进PSA向IND申请作为一种安全和 有效的口服一流治疗人类炎症性肠病。该项目包括3 具体目标：在具体目标1中，我们将扩展初步的人体体外疗效研究， PSA将初始T细胞转化为分泌抗炎IL-10的Treg细胞的能力， 评估PSA对取自炎症性肠病患者的PBMC和肠道组织的影响。在 具体目标2，我们将与生物制药合同制造商合作，扩大生产规模 我们已优化的工艺，可生产200 L批次，支持IND支持GLP 毒理学研究。在具体目标3中，我们将开展分析方法开发，以支持规模扩大， 生产毒性研究和临床试验所需的大量材料。这些具体目标将 为PSA进入IND备案和I期临床试验奠定必要的基础。随着我们公司 致力于将开创性的学术研究转化为第一个治疗分子， 从人类微生物组中产生，2期STTR支持将推动这一革命性的治疗选择 将IBD推向人类临床试验的边缘，并将为PSA应用于其他免疫系统铺平道路。 介导的疾病，如多发性硬化症、哮喘和类风湿性关节炎。