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 这个项目的目标是开发一种小分子药物，作为一种新的肠道调节疗法。 炎症性肠病(IBD)患者的生物失调。超过160万美国人患有IBD，一种 用于描述包括克罗恩病在内的全部或部分消化道的慢性炎症的总称 和溃疡性结肠炎。IBD是一种复杂的免疫疾病，可由遗传、环境、异常 免疫反应和消化道微生物区系的破坏。IBD跻身全球最贵的五大品牌之一 胃肠道疾病，每年直接医疗费用负担在110亿至280亿美元之间，大约一半 这些都是处方药。目前管理或治疗IBD的策略包括抑制免疫 然而，这些药物中的许多都不是长期使用的，其他药物在一半以上都没有效果。 接受治疗的患者的比例。因此，目前可用的治疗方法并不能满足所有患者和新的 治疗方法是必要的。Symberix，Inc.正在开发一类新型小分子药物 特别针对和抑制消化道炎症的已知原因之一：微生物群。引航员 研究证实了阻断细菌β-葡萄糖苷酸酶(GUS)活性的初步可行性 在不影响保护性细菌生长的情况下，减缓有害细菌的生长。 小分子GUS抑制剂在使用来自于 IBD患者。这一阶段的提案将侧重于确认和扩大试点研究，通过严格的 两种候选小分子药物在小鼠体内溃疡性溃疡模型中的生物活性评价 结肠炎和使用IBD患者粪便样本的体外抑制试验。