Small molecule drugs targeting gut dysbiosis to manage inflammatory bowel disease

针对肠道菌群失调的小分子药物治疗炎症性肠病

• 批准号: 10481382
• 负责人: Bret David Wallace
• 金额: $ 30.46万
• 依托单位: SYMBERIX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2023-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481382
• 关键词: Adult; American; Animal Disease Models; Anti-Inflammatory Agents; Antigen-Antibody Complex; Back; Bacteria; Beta-glucuronidase; Biological; Biological Assay; Biological Markers; Biological Products; Chronic; Clinical Research; Colitis; Communities; Complement; Control Groups; Crohn' s disease; Data; Development; Disease; Disease Marker; Disease Pathway; Dose; Drug Prescriptions; Drug Targeting; Enterobacteriaceae; Environment; Enzymes; Exhibits; Feces; Future; Gastrointestinal tract structure; Genetic; Glucuronidase Inhibitor; Goals; Growth; Human; Human body; Immune; Immune System Diseases; Immune response; Immune system; Indomethacin; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Knock-out; Lead; Life; Link; Maintenance; Malignant - descriptor; Measures; Mediating; Mediator of activation protein; Medical Care Costs; Modeling; Mus; Nature; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Plant Roots; Population; Proteins; Rattus; Reporting; Research; Risk; Sampling; Series; Shotguns; Testing; Therapeutic; Treatment outcome; Ulcerative Colitis; Work; analog; clinically relevant; compound 30; cost effective; disease phenotype; drug discovery; efficacy evaluation; first-in-human; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; improved; in vivo; infection risk; inflammatory marker; inhibitor; lead candidate; metagenomic sequencing; microbial; microbiome; microbiome composition; microbiota; mouse model; murine colitis; novel; novel therapeutics; pre-clinical; preclinical study; protective effect; side effect; small molecule; small molecule inhibitor; stool sample; success; sugar; targeted treatment; therapeutically effective; volunteer

Project Summary The goal of this project is to develop a small molecule drug as a novel therapeutic for the modulation of gut dysbiosis in patients with inflammatory bowel disease (IBD). Over 1.6 million Americans suffer from IBD, an umbrella term used to describe chronic inflammation of all or part of the digestive tract, including Crohn’s disease and ulcerative colitis. IBD is a complex immune disorder that can be caused by genetics, environment, aberrant immune response and disruption of the digestive tract microbiota. IBD ranks as one of the five most expensive GI disorders, with an annual direct medical cost burden between 11 and 28 billion dollars, approximately half of which are for prescription drugs. Current strategies to manage or treat IBD involve suppressing the immune system, however many of these drugs are not intended for long term use, and others have no effect in up to half of patients treated. Therefore, currently available therapies do not meet the needs of all patients and new treatment approaches are needed. Symberix, Inc. is developing a novel class of small molecule drugs that specifically target and inhibit one of the known causes of digestive tract inflammation: the microbiome. Pilot studies demonstrate the preliminary feasibility of blocking the activity of bacterial beta glucuronidases (GUS enzymes) and slowing the growth of harmful bacteria without compromising the growth of protective bacteria. Small molecule GUS inhibitors also show potent activity in ex vivo assays using biological samples derived from patients with IBD. This Phase I proposal will focus on confirming and extending pilot studies by rigorously evaluating the biological activity of two candidate small molecule drugs in an in vivo mouse model of ulcerative colitis and an ex vivo inhibition assay using IBD patient-derived stool samples.

项目摘要 该项目的目的是开发一种小分子药物作为调节肠的新疗法 患有炎症性肠病（IBD）患者的营养不良。超过160万美国人患有IBD 用来描述全部或部分消化道的慢性炎症的伞术，包括克罗恩病 和溃疡性结肠炎。 IBD是一种复杂的免疫疾病，可能是由遗传学，环境，异常引起的 IBD排名为最昂贵的五个 胃肠道疾病，年度直接医疗费用耗尽了11至280亿美元，约有一半 用于处方药。当前管理或治疗IBD的策略涉及抑制免疫力 系统，这些药物中的许多不打算长期使用，其他药物最多没有影响 接受治疗的患者。因此，目前可用的疗法并不满足所有患者的需求 需要治疗方法。 Symberix，Inc。正在开发一种新型的小分子药物 飞行员专门针对并抑制了消化道注射的已知原因之一：微生物组。 研究表明，阻断细菌β葡萄糖醛酸酶（GUS）活性的初步可行性 酶）并减慢有害细菌的生长，而不会损害保护细菌的生长。 小分子GUS抑制剂还使用从 IBD患者。该阶段我的提议将重点侧重于确认和扩展试点研究 评估在溃疡内体内小鼠模型中两种候选小分子药物的生物学活性 结肠炎和使用IBD患者衍生的粪便样品的体内抑制测定法。