Small molecule drugs targeting gut dysbiosis to manage inflammatory bowel disease

项目摘要 该项目的目标是开发一种小分子药物作为调节肠道的新型治疗药物 炎症性肠病（IBD）患者的肠道菌群失调。超过160万美国人患有IBD， 用于描述全部或部分消化道慢性炎症的总称，包括克罗恩病 和溃疡性结肠炎IBD是一种复杂的免疫系统疾病，可由遗传、环境、异常免疫系统和免疫缺陷引起。 免疫反应和消化道微生物群的破坏。IBD是世界上最昂贵的五种疾病之一。 胃肠道疾病，每年的直接医疗费用负担在110亿至280亿美元之间，约占全球医疗费用的一半。 这是处方药。目前管理或治疗IBD的策略包括抑制免疫抑制剂的产生。 然而，这些药物中的许多并不打算长期使用，其他药物在高达一半的时间内没有效果。 治疗的病人。因此，目前可用的疗法不能满足所有患者的需求，并且新的治疗方法不能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， 特异性靶向和抑制消化道炎症的已知原因之一：微生物组。试点 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）和减缓有害细菌的生长而不损害保护性细菌的生长。 小分子GUS抑制剂还在使用来源于以下的生物样品的离体测定中显示出有效的活性： IBD患者第一阶段的建议将侧重于确认和扩大试点研究， 评价两种候选小分子药物在溃疡性结肠炎的体内小鼠模型中的生物活性 结肠炎和使用IBD患者来源的粪便样品的离体抑制测定。

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.