Therapeutics for inflammatory bowel disease from the microbiome

从微生物组治疗炎症性肠病

• 批准号: 8777885
• 负责人: Sarkis K Mazmanian
• 金额: $ 39.68万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777885
• 关键词: Adverse effects; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antigens; Area; Asthma; Award; Bacteria; Bacteroides fragilis; Binding; Biodistribution; Biological; Biological Assay; Biological Response Modifier Therapy; Biology; Biotechnology; Blood Circulation; California; Cells; Chronic; Clinical; Clinical Trials; Coculture Techniques; Colitis; Collection; Complex; Data; Dendritic Cells; Development; Disease; Disease Management; Disease Progression; Disease model; Doctor of Philosophy; Dose; Drug Kinetics; Engineering; Etiology; Experimental Models; Foundations; Funding; Gastrointestinal Diseases; Goals; Grant; Haplotypes; Human; Human Microbiome; Human body; Immune; Immune response; Immune system; Immunosuppression; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Institutes; Interleukin-10; Intestines; Investigational Drugs; Life; Ligands; Link; Mediating; Medical; Membrane; Microbe; Modeling; Multiple Sclerosis; Mus; Oral; Oral Administration; Organism; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Polysaccharides; Population; Pre-Clinical Model; Process; Psoriasis; Publishing; Radiolabeled; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Rheumatoid Arthritis; Role; Safety; Sampling; Science; Serious Adverse Event; Signal Transduction; Small Business Technology Transfer Research; Staging; Steroids; Structure; Symptoms; T cell therapy; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Therapeutic; Therapeutic Agents; Therapeutic immunosuppression; Tissues; Toll-Like Receptor 2; Toxicology; Translating; United States; Vesicle; Work; base; effective therapy; germ free condition; human data; human disease; in vivo; manufacturing process; medical complication; medical schools; microbial; microbiome; microorganism; mouse model; next generation; novel; novel strategies; preclinical efficacy; preclinical study; prevent; professor; programs; protective effect; public health relevance; radiotracer; receptor; single molecule; translational study

DESCRIPTION (provided by applicant): 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 several approved immunosuppressive therapies, often leading to toxic side effects. Symbiotix Biotherapies, Inc. is a startup biotechnology company developing a first-in-class therapeutic agent for IBD 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 interleukin (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. 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 mouse colitis 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 oral first-in-class treatment for IBD. The project consists of 3 Specific Aims: In Specific Aim 1, we will expand on initial in vivo efficacy studies of oral PSA in a murine colitis model to evaluate the effect of PSA in dose-escalating efficacy studies. In Specific Aim 2, we will radiolabel PSA and carry out PK/biodistribution studies of orally-administered PSA. In Specific Aim 3, we will carry out HLA haplotype restriction studies to evaluate the ability of PSA to modulate human cells of the major HLA haplotypes. Successful completion of this Phase 1 STTR project will generate the preclinical efficacy data, biodistribution data and HLA haplotype restriction data 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 these 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 IBD, but may also pave the way for application of PSA to other immune- mediated diseases such as multiple sclerosis, asthma, psoriasis and / or rheumatoid arthritis.

描述（由申请人提供）：肠道微生物组和免疫系统之间的相互作用与炎症性肠病（IBD）有关。 IBD 是一种慢性进行性胃肠道疾病，其特征是肠道免疫系统不受控制的激活，导致严重的医疗并发症，影响美国超过 150 万患者。这是一种医疗需求未得到满足的疾病，目前只能用几种已批准的免疫抑制疗法中的一种来治疗，通常会导致毒副作用。 Symbiotix Biotherapies, Inc. 是一家初创生物技术公司，根据最近从人类微生物组中得出的发现，开发用于 IBD 和其他免疫介导疾病的一流治疗剂。我们的科学创始人发现了一种特定的肠道共生生物，即脆弱拟杆菌，它能诱导白细胞介素 (IL)-10 分泌调节性 T 细胞 (Treg) 能够抑制 T 细胞 Th1、Th2 和 Th17 亚群的促炎活性。此外，我们还从这种生物体中鉴定出一种负责保护作用的特定荚膜多糖 (PSA)，表明 PSA 通过 Treg 激活的新机制发挥作用，以扩大小鼠体内的抗炎 T 细胞群，并表明口服纯化 PSA 对多种小鼠结肠炎模型具有保护作用。我们这一阶段 STTR 项目的目标是进行关键的转化研究，这对于推进 PSA 作为 IBD 的安全有效的口服一流治疗药物进行 IND 申报至关重要。该项目由 3 个具体目标组成：在具体目标 1 中，我们将扩展小鼠结肠炎模型中口服 PSA 的初步体内功效研究，以评估 PSA 在剂量递增功效研究中的效果。在具体目标2中，我们将对PSA进行放射性标记并进行口服PSA的PK/生物分布研究。在具体目标3中，我们将进行HLA单倍型限制研究，以评估PSA调节主要HLA单倍型人类细胞的能力。第一阶段 STTR 项目的成功完成将产生临床前疗效数据、生物分布数据和 HLA 单倍型限制数据，以证明快速推进 IND 申请的合理性，该申请将在后续第二阶段 STTR 资金的支持下将 PSA 纳入人体临床试验。随着我们公司致力于转化这些开创性的学术研究，从人类微生物组中产生第一个治疗分子，第一阶段的 STTR 支持不仅将为开发 IBD 的革命性治疗方案奠定基础，而且还可能为 PSA 应用于其他免疫介导疾病（如多发性硬化症、哮喘、牛皮癣和/或类风湿性关节炎）铺平道路。