Therapeutics for inflammatory bowel disease from the microbiome

项目摘要/摘要 肠道微生物群和免疫系统之间的相互作用与炎症性肠炎有关 疾病(IBD)。IBD是一种慢性进行性胃肠道疾病，以失控为特征 激活肠道免疫系统，导致严重的医疗并发症，影响150多万人 在美国的病人。这是一种高度未得到满足的医疗需求的疾病，目前只有一种方法可以治疗 12种已获批准的免疫抑制疗法，通常会导致毒副作用。共生生物治疗公司 是一家早期生物技术公司，为IBD和其他疾病开发一流的治疗剂 基于人类微生物组的最新发现的免疫介导性疾病。我们的科学研究 创始人们已经确定了一种特定的肠道共生微生物，脆弱类杆菌，它能诱导白细胞介素2- 10-分泌调节性T细胞(Tregs)，能够抑制Th1，Th2和Th2的促炎活性 Th17 T细胞亚群。我们还从中鉴定出一种特殊的胶囊多糖(PSA)。 负责保护作用的微生物，表明PSA通过一种新的Treg机制工作 激活以扩大小鼠抗炎T细胞群，并显示口服纯化的 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项目的目标是进行 对于推动PSA向IND备案至关重要的关键翻译活动 对人类炎症性肠病有效的口服一流治疗。该项目由3个部分组成 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，这些研究证明 PSA在分泌抗炎IL-10的培养中将幼稚T细胞转化为Treg细胞的能力 评价PSA对炎症性肠病患者PBMC和肠道组织的影响。在……里面 具体目标2，我们将与一家生物制药合同制造商合作，扩大生产规模 我们已经优化的工艺，能够生产200L批次，能够支持IND-Enabling GLP 毒理学研究。在具体目标3中，我们将开展分析方法开发，以支持规模扩大和 生产大量毒理研究和临床试验所需的材料。这些具体目标将 为PSA进入IND申请和I期临床试验奠定必要的基础。作为我们的公司 致力于将导致第一个治疗分子的开创性学术研究转化为 从人类微生物群中脱颖而出的第二阶段STTR支持将推动这一革命性的治疗选择 为IBD走向人类临床试验的边缘，并将为PSA在其他免疫领域的应用铺平道路。 中介疾病，如多发性硬化症、哮喘和类风湿性关节炎。

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.