Novel commensal polysaccharide treats multiple sclerosis through Treg modulation

新型共生多糖通过 Treg 调节治疗多发性硬化症

• 批准号: 8647277
• 负责人: LLOYD H KASPER
• 金额: $ 32.29万
• 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: 2014-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647277
• 关键词: Ablation; Adverse effects; Adverse event; Affect; Antibiotics; Antigens; Arrhythmia; Asthma; Bacteroides fragilis; Biodistribution; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biology; Biotechnology; Blood; Cells; Cervical lymph node group; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Colitis; Collection; Data; Demyelinating Diseases; Demyelinations; Dendritic Cells; Development; Disease; Disease Management; Disease Progression; Disease model; Distal; Dose; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; FDA approved; Feces; Frequencies; Funding; Germ-Free; Goals; Grant; Gut associated lymphoid tissue; Homeostasis; Human; Human Microbiome; Human body; Immune; Immune Tolerance; Immune system; Immunology; Immunosuppression; Industry; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon-beta; Interleukin-10; Intestines; Investigational Drugs; Lead; Life; Ligation; Lymphoid Tissue; Lymphopenia; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Medical; Medicine; Methodology; Microbe; Microbiology; Modeling; Monoclonal Antibodies; Mouse Strains; Multiple Sclerosis; Mus; Neuraxis; Opportunistic Infections; Oral; Oral Administration; Organism; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Plasma; Polysaccharides; Population; Predisposition; Preparation; Publishing; Reagent; Regulation; Regulatory T-Lymphocyte; Relapse; Research Personnel; Rheumatoid Arthritis; Role; SJL Mouse; Safety; Science; Serious Adverse Event; Severities; Signal Transduction; Small Business Technology Transfer Research; Societies; Staging; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Agents; Toll-Like Receptor 2; Toxic effect; Toxicology; Translating; Translations; United States National Institutes of Health; Urine; Work; alemtuzumab; alternative treatment; base; commensal microbes; copolymer 1; design; effective therapy; frontier; gut microbiota; gut microflora; high risk; human data; human disease; immunoregulation; in vivo; lymph nodes; manufacturing process; medical schools; microbial; microbiome; microorganism; migration; natalizumab; nervous system disorder; next generation; novel; novel strategies; preclinical efficacy; preclinical safety; preclinical study; professor; programs; protective effect; public health relevance; rituximab; single molecule; tool; translational study; young adult

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.

抽象的 多发性硬化症（MS）是一种慢性脱髓鞘性炎症性疾病，是最常见的神经系统 年轻人的疾病，在美国影响超过35万名患者，全球超过250万患者。多发性硬化症 是一种高未满足医疗需求的疾病，目前可以用几种认可的药物之一来治疗 导致免疫调节或明显的免疫抑制或免疫消融，可能导致 严重的不利影响，包括机会性感染和恶性肿瘤。 Symbiotix Biotherapies，Inc。是 启动生物技术公司开发了一种用于MS和其他免疫力的第一类治疗剂 基于最近从人类微生物组中出现的发现的介导疾病。我们的科学 创始人已经确定了一种特定的肠道生物体，即fragilis，可诱导IL-10分泌 能够抑制Th1，Th2和Th17子集的促炎活性的调节T细胞（Treg） T细胞。他们还确定了特定的细菌囊多糖（PSA） 负责保护作用的有机体，表明PSA通过Treg的新型机制起作用 激活以扩大无菌和常规小鼠的T细胞群体，并表明口服 纯化的PSA的给药可抵抗多个小鼠结肠炎和实验过敏性 脑脊髓炎（EAE）模型。我们对此阶段1 STTR项目的目标是进行关键的翻译 对于将PSA推向IND归档至关重要的研究是安全有效的新口头 MS的治疗。该项目由3个特定目标组成：在特定目标1中，我们将扩展初始体内 口服PSA在鼠EAE模型中的疗效研究，以评估PSA在剂量降低功效中的影响 对EAE诱导的两种小鼠菌株的研究。在特定目标2中，我们将开发药效读数 PSA在小鼠血浆，PBMC和淋巴组织中的作用，将用作临床前的生物标志物 和临床研究，还开发了一种抗PSA单克隆抗体，该抗体将用于直接测量 血浆，尿液和粪便中的PSA。在特定目标3中，我们将使用小鼠评估PSA的潜在毒性 最大耐受剂量（MTD）研究。成功完成此阶段1 sttr项目将产生 临床前疗效数据，安全数据和生物分析工具，以证明快速推动IND归档的必要合理性 这将使PSA在后续II期STTR资金的支持下将PSA带入人类临床试验。作为我们的 公司致力于翻译开创性的学术研究，这些研究导致了第一种治疗 从人类微生物组中出现的分子，第1阶段的STTR支持不仅会为 为MS开发革命性的治疗选择，但也将为将PSA应用于 其他免疫介导的疾病，例如炎症性肠病，哮喘和类风湿关节炎。