Novel commensal polysaccharide treats multiple sclerosis through Treg modulation

 描述(申请人提供)：多发性硬化症(MS)是一种慢性脱髓鞘炎症性疾病，是年轻人最常见的神经系统疾病，影响美国超过45万名患者和全球超过350万名患者。MS是一种高度未得到满足的疾病，目前可用FDA批准的12种药物中的一种来治疗，所有这些药物都会导致显著的免疫抑制、免疫调节或免疫消融，从而导致严重的不良反应，包括机会性感染，如PML、恶性肿瘤、胃肠道功能障碍、肝脏变化、可能的胎儿畸形、注射部位反应和血液代谢不良。随着治疗这种慢性炎症性疾病的管道扩大，寻求更强大的疗效，与之相关的对长期安全性和耐受性的担忧也随之增加。SymBiotix BioTreatures，Inc.是一家初创生物技术公司，基于人类微生物组最近的发现，开发一种治疗多发性硬化症和其他免疫介导性疾病的一流治疗剂。我们的科学创始人已经发现了一种特定的肠道共生微生物，脆弱类杆菌，它可以诱导分泌IL-10的调节性T细胞(Treg)，从而能够抑制促炎反应。他们进一步从这种微生物中鉴定出一种负责保护作用的特定细菌荚膜多糖(PSA)，并表明口服纯化的PSA对多种小鼠实验性变态反应性脑脊髓炎(EAE)模型具有保护作用。我们最近的研究由第一阶段STTR资助，完成了剂量范围疗效研究和MTD研究，并确定了PSA效应的药效学标记。总之，小鼠研究表明，PSA是免疫调节反应的强大调节器，可能在治疗人类多发性硬化症方面有效。我们这个第二阶段STTR项目的目标是进行关键的翻译研究，这对于推动PSA成为一种安全有效的治疗多发性硬化症的新口服疗法至关重要。该项目包括三个具体目标：在特定目标1，我们将扩展最初的人类体外疗效研究，证明PSA在培养中将幼稚的T细胞转化为Treg细胞的能力，该细胞在培养中分泌IL-10和各种抗炎分子。为了评估PSA对特定目的2的MS患者PBMC的影响，我们将在已发表的小鼠疗效研究和第一阶段STTR结果的基础上，利用EAE的非人类灵长类动物模型评估PSA在第二物种疗效研究中的效果。在具体目标3中，我们将生产用于第一阶段人体临床试验的cGMP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。随着我们公司致力于将突破性的学术研究转化为人类微生物组中出现的第一个治疗分子，第二阶段STTR支持将把这一针对多发性硬化症的革命性治疗方案推向人类临床试验的边缘，并将为将PSA应用于其他免疫调节疾病铺平道路，如炎症性肠道疾病、哮喘和类风湿性关节炎。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease that is the most common neurological disease of young adults, affecting over 450,000 patients in the US and over 3.5 million patients worldwide. MS is a disease of high unmet medical need, currently treatable with one of twelve FDA approved drugs, all of which result in either significant immunosuppression, immune modulation or immune ablation that can lead to serious adverse effects including opportunistic infections such as PML, malignancy, GI disturbance, hepatic changes, possible fetal teratogenicity, injection site reactions and blood dyscrasias. As the pipeline for treating this chronic inflammatory condition has expanded in a search for more robust efficacy, so have the associated concerns surrounding long term safety and tolerance. 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 response. They have furthermore identified a specific bacterial capsular polysaccharide (PSA) from this organism responsible for the protective effect, and shown that oral administration of purified PSA is protective against multiple mouse experimental allergic encephalomyelitis (EAE) models. Our recent studies funded by the Phase I STTR completed dose-ranging efficacy studies, MTD studies and identified a pharmacodynamic marker of PSA effect. Together, the mouse studies suggest that PSA is a robust modulator of the immune regulatory response that may be effective in the treatment of human MS. Our objective for this Phase 2 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 human in vitro efficacy studies that demonstrate the capacity of PSA to convert naïve T cells into Treg cells in culture that secrete IL-10 and a variey of anti-inflammatory molecules, to evaluate the effect of PSA on PBMCs taken from patients with MS. In Specific Aim 2, we will build on published mouse efficacy studies and results from the Phase 1 STTR to evaluate the effect of PSA in second species efficacy studies using a non-human primate model of EAE. In Specific Aim 3, we will produce cGMP material that will be used in Phase 1 human 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 MS to the brink of human clinical trials, and will pave the way for applicatio of PSA to other immune-mediated diseases such as inflammatory bowel disease, asthma and rheumatoid arthritis.