Preclinical validation of small molecule immunomodulators for the treatment of Crohn's disease

项目摘要 克罗恩病是一种衰弱的慢性胃肠道炎症性疾病，其特征是 异常愈合和肠管狭窄。在美国，50多万名克隆氏病患者 每年新诊断的患者有3万人。目前还没有根治方法。相反，目前的治疗方法侧重于 关于管理症状和减少新发作的发生。迫切需要新的治疗方法。 我们假设，肠粘膜屏障和局部免疫信号的靶向调节在 肠道可以逆转疾病的发展。调节免疫和粘膜愈合的一种有希望的方法是 利用胃肠道共生细菌释放的分子作为免疫系统 已经进化出与这些分子相互作用的特定方式。不过，除了一些初步数据显示， 这些分子对小鼠急性肠炎有保护作用，这些免疫调节的作用 治疗肠炎的分子仍不清楚。我们已经开发出一种新的分子，灵感来自于 这些细菌分子显示出增强了对腹膜内肠炎的保护作用 注射于急性肠炎小鼠模型。然而，目前还不清楚我们的分子是否可以 口服而不是注射的。因此，在这个项目的第一部分，我们将评估治疗 我们的分子对急性肠炎小鼠口服给药的影响。 接下来，由于急性肠炎模型只模拟疾病的某些方面，无法捕捉到 在克罗恩病中观察到的多方面、慢性、进行性炎症，我们将进一步验证 我们的分子是否为克罗恩病提供了一种有前途的治疗策略 对自发发展的慢性肠道遗传小鼠模型的治疗作用的分子研究 发炎。这种小鼠模型依赖于mdr1a基因中的一种工程遗传缺陷。MDR1a扮演着 在调节肠粘膜先天免疫和获得性免疫中的作用。在基因失活时 Mdr1a，小鼠在8-14周龄时出现慢性肠炎，更接近于 发生在克罗恩病患者身上的比化学诱导的急性模型。因此，这个MDR1a-/-的结果是积极的 小鼠模型将为我们这类分子治疗克罗恩病的效用提供进一步的验证。 在这些研究完成后，我们希望已经确定我们的分子是否可以用于 以及它是否能保护小鼠免受与克罗恩病更相似的慢性肠炎的侵袭 疾病。这些研究的结果对于确定药物开发过程中的下一步至关重要 我们的分子旨在开发一种易于使用的肠道导向治疗克罗恩病的药物。这 这一点很重要，因为目前克罗恩病的治疗方案显示疗效有限，而且通常需要 (自我)-注射。克罗恩病患者期待新的、实用的、非免疫抑制的药物。

Project Summary Crohn’s disease is a debilitating and chronic inflammatory disorder of the gastrointestinal tract characterized by aberrant healing and intestinal stricturing. In the US, >500,000 patients suffer from Crohn’s disease and over 30,000 patients are newly diagnosed each year. No curative treatments exist. Instead, current treatments focus on managing symptoms and reducing the occurrence of new episodes. New treatments are urgently needed. We hypothesize that targeted modulation of the intestinal mucosal barrier and local immune signaling in the bowel can reverse disease progression. A promising way to modulate immunity and mucosal healing is utilizing molecules that are released by commensal bacteria in the gastrointestinal tract as the immune system has evolved specific ways to interact with these molecules. However, besides some preliminary data showing that such molecules protect against acute bowel inflammation in mice, the utility of these immunomodulatory molecules for treating bowel inflammation remains unclear. We have developed a new molecule inspired by these bacterial molecules that shows improved protection against bowel inflammation upon intraperitoneal injection in an acute mouse model of bowel inflammation. However, it is unclear whether our molecule can be administered orally instead of by injection. Thus, in the first part of this project, we will evaluate the therapeutic effect of our molecule upon oral administration in mice experiencing acute bowel inflammation. Next, as acute models of bowel inflammation only mimic certain aspects of disease and fail to capture the multi-faceted, chronic, progressive inflammation observed in Crohn’s disease, we will further validate whether our molecule provides a promising therapeutic strategy for Crohn’s disease by examining our molecule for its therapeutic effect in a genetic mouse model of spontaneously developing, chronic bowel inflammation. This mouse model relies on an engineered genetic defect in the Mdr1a gene. MDR1A plays a role in the regulation of innate and adaptive immunity in the intestinal mucosa. Upon genetic inactivation of Mdr1a, mice develop chronic bowel inflammation at 8-14 weeks of age that more closely resembles what occurs in Crohn’s disease patients than chemically induced acute models. Thus, positive results in this Mdr1a-/- mouse model will provide further validation for the utility of our class of molecules for treating Crohn’s disease. At the completion of these studies, we expect to have determined whether our molecule can be used orally and whether it can protect mice from chronic bowel inflammation that more closely resembles Crohn’s disease. The results from these studies are critical to define the next steps in the drug development process of our molecule, which is aimed at developing an easy-to-use, gut directed therapeutic for Crohn’s disease. This is important because current treatment options for Crohn’s disease show limited efficacy and often require (self)-injection. Crohn’s patients look forward to new and practical, non-immunosuppressive drugs.