Therapeutics for inflammatory bowel disease from the microbiome

从微生物组治疗炎症性肠病

基本信息

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
项目类别：
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

项目摘要

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）：肠道微生物组与免疫系统之间的相互作用与炎症性肠病（IBD）有关。 IBD是一种慢性和进行性胃肠道疾病，其特征是肠道免疫系统的激活不受控制，导致严重的医疗并发症，影响了美国超过150万患者。这是一种高未满足的医疗需求的疾病，目前只能使用几种认可的免疫抑制疗法之一来治疗，通常会导致有毒副作用。 Symbiotix Biotherapies，Inc。是一家创业生物技术公司，开发了基于最近从人类微生物组中出现的发现的IBD和其他免疫介导的疾病的第一类治疗剂。我们的科学创始人已经确定了特定的肠道共生生物，诱导白介素（IL）-10分泌调节T细胞（TREG）的细菌性脆弱性能够抑制T细胞Th1，Th2和Th17子集的促炎活性。此外，我们还从该生物体中确定了负责保护性效果的特定囊囊多糖（PSA），这表明PSA通过Treg激活的新机制起作用，以扩大小鼠的抗炎T细胞群体，并表明口服纯化的PSA的口服给药。在多个小鼠结肠炎模型中具有保护性。我们对这一阶段1 STTR项目的目标是进行关键的翻译研究，这对于将PSA推进到IND归档至关重要，作为安全有效的IBD口服一流的口服治疗。该项目由3个特定目的组成：在特定的目标1中，我们将在鼠结肠炎模型中对口服PSA的初始体内功效研究进行扩展，以评估PSA在剂量降低疗效研究中的影响。在特定的目标2中，我们将对口腔管理PSA进行放射性标记PSA并进行PK/生物分布研究。在特定目标3中，我们将进行HLA单倍型限制研究，以评估PSA调节主要HLA单倍型的人类细胞的能力。该阶段1 STTR项目的成功完成将生成临床前疗效数据，生物分布数据和HLA单倍型限制数据，以证明快速推动IND归档的合理性，该数据将PSA将PSA带入人类临床试验，并支持后续II期STTR资金。。由于我们公司致力于翻译这些开创性的学术研究，这些研究导致了第一个从人类微生物组中出现的治疗分子，因此，第一阶段的STTR支持不仅将为IBD开发革命性治疗方案提供基础，而且还可以铺路将PSA应用于其他免疫介导的疾病（例如多发性硬化症，哮喘，牛皮癣和 /或类风湿关节炎）的方法。