Novel commensal polysaccharide treats multiple sclerosis through Treg modulation

摘要 多发性硬化(MS)是一种慢性脱髓鞘炎症性疾病，是最常见的神经系统疾病 年轻人的疾病，影响到美国超过350,000名患者和全球超过250万名患者。女士 是一种高度未得到满足的医疗需求的疾病，目前可以用几种批准的药物中的一种来治疗，所有这些药物 导致免疫调节或显著的免疫抑制或免疫消融，可导致 严重的不良反应，包括机会性感染和恶性。共生生物治疗公司是一家 一家初创生物技术公司开发一流的多发性硬化症和其他免疫疾病的治疗剂 基于最近从人类微生物组中发现的介导性疾病。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，它可以诱导IL-10的分泌 能够抑制Th1、Th2和Th17亚群的促炎活性的调节性T细胞(Treg) T细胞的数量。他们还进一步确定了一种特殊的细菌荚膜多糖(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 激活以扩大无菌小鼠和常规小鼠的T细胞群，并表明口服 纯化PSA对多发性小鼠结肠炎和实验性变态反应的保护作用 脑脊髓炎(EAE)模型。我们第一阶段STTR项目的目标是进行关键的翻译 对于推动PSA成为安全有效的新口腔药物的IND备案至关重要的研究 MS的治疗项目包括3个具体目标：在具体目标1中，我们将在体内初步展开 口服PSA在小鼠EAE模型中的疗效研究评价PSA的剂量递增效应 两种品系小鼠诱发EAE的研究。在特定目标2中，我们将开发一个药效学读数 PSA在小鼠血浆、PBMC和淋巴组织中的作用将作为临床前生物标志物的研究 和临床研究，并开发出一种抗PSA的单抗，将用于直接检测 血浆、尿液和大便中的PSA。在特定目标3中，我们将使用小鼠评估PSA的潜在毒性 最大耐受量(MTD)研究。这一第一阶段STTR项目的成功完成将产生 临床前疗效数据、安全性数据和生物分析工具，以证明快速推动IND申请是合理的 这将在第二阶段STTR资金的支持下，将PSA带入人体临床试验。作为我们的 该公司致力于将开创性的学术研究转化为第一个治疗性研究 分子从人类微生物群中脱颖而出，第一阶段STTR的支持不仅将为 开发一种革命性的多发性硬化症治疗方案，但也将为PSA在 其他免疫调节疾病，如炎症性肠病、哮喘和类风湿性关节炎。

Abstract Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease that is the most common neurological disease of young adults, affecting over 350,000 patients in the US and over 2.5 million patients worldwide. MS is a disease of high unmet medical need, currently treatable with one of several approved drugs, all of which result in either immune modulation or significant immunosuppression or immune ablation that can lead to serious adverse effects including opportunistic infections and malignancy. Symbiotix Biotherapies, Inc. is a startup biotechnology company developing a first-in-class therapeutic agent for MS and other immune- mediated diseases based on discoveries recently emerging from the human microbiome. Our scientific founders have identified a specific gut commensal organism, Bacteroides fragilis, that induces IL-10-secreting regulatory T cells (Treg) that are able to dampen the pro-inflammatory activities of Th1, Th2 and Th17 subsets of T cells. They have furthermore identified a specific bacterial capsular polysaccharide (PSA) from this organism responsible for the protective effect, shown that PSA works through a novel mechanism of Treg activation to expand T cell populations in both germ-free and conventional mice, and shown that oral administration of purified PSA is protective against multiple mouse colitis and experimental allergic encephalomyelitis (EAE) models. Our objective for this Phase 1 STTR project is to conduct key translational studies that will be essential for advancing PSA towards an IND filing as a safe and efficacious new oral treatment for MS. The project consists of 3 Specific Aims: In Specific Aim 1, we will expand on initial in vivo efficacy studies of oral PSA in the murine EAE model to evaluate the effect of PSA in dose-escalating efficacy studies in two strains of mice induced for EAE. In Specific Aim 2, we will develop a pharmacodynamic readout of PSA's effect in mouse plasma, PBMC and lymphoid tissue that will be used as a biomarker for preclinical and clinical studies, and also develop an anti-PSA monoclonal antibody that will be used to directly measure PSA in plasma, urine and stool. In Specific Aim 3, we will evaluate the potential toxicity of PSA using mouse maximal tolerated dose (MTD) studies. Successful completion of this Phase 1 STTR project will generate the preclinical efficacy data, safety data and bioanalytical tools necessary to justify a rapid push towards IND filing that will take PSA into human clinical trials with the support of follow-on Phase II STTR funding. 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 1 STTR support will not only lay the groundwork for the development of a revolutionary treatment option for MS, but will also pave the way for application of PSA to other immune-mediated diseases such as inflammatory bowel disease, asthma and rheumatoid arthritis.