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

小分子免疫调节剂治疗克罗恩病的临床前验证

• 批准号: 10600659
• 负责人: Aikaterini Chatzi
• 金额: $ 27.19万
• 依托单位: PROMAKHOS THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600659
• 关键词: ABCB1 gene; Acclimatization; Acetylmuramyl-Alanyl-Isoglutamine; Acute; Address; Affect; Age; Agonist; Bacteria; Biological; Biological Sciences; Blood; Body Weight; Cell physiology; Chemicals; Chronic; Clinic; Colitis; Colon; Colonic inflammation; Control Groups; Crohn' s disease; Data; Development; Diarrhea; Digestive System Disorders; Disease; Disease Progression; Dose; Drug Exposure; Drug Kinetics; Endoscopy; Etiology; Euthanasia; Excretory function; FOXP3 gene; Feces; Felis catus; Friends; Gastrointestinal tract structure; Genes; Genetic; Genetic Engineering; Hematochezia; Histopathology; IL8 gene; Immune signaling; Immune system; Immunity; Impairment; Inflammation; Inflammatory; Injections; Innate Immune Response; Innate Immune System; Interferon Type II; Interleukin-1 beta; Interleukin-10; Interleukin-12; Intestinal Mucosa; Intestines; Intraperitoneal Injections; Knock-out; Knockout Mice; Lead; Length; Ligands; Measurement; Measures; Mitochondria; Modeling; Monitor; Mucous Membrane; Mus; Mutation; Natural Immunity; Nature; Newly Diagnosed; Onset of illness; Oral; Oral Administration; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Route; Signal Transduction; Sodium Dextran Sulfate; TLR4 gene; TNF gene; The Jackson Laboratory; Therapeutic; Therapeutic Effect; Time; Toxin; Urine; Validation; Wild Type Mouse; adaptive immunity; analog; commensal bacteria; curative treatments; cytokine; dextran sulfate sodium induced colitis; drinking water; drug development; efficacy evaluation; experience; gut inflammation; healing; immunomodulatory therapies; immunoregulation; improved; in vivo; intestinal barrier; intraperitoneal; mouse model; novel therapeutic intervention; novel therapeutics; pre-clinical; protective effect; prototype; small molecule; small molecule therapeutics; standard of care; symptom management; treatment group; treatment strategy; wound healing

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.

项目摘要 克罗恩病是一种胃肠道的衰弱性和慢性炎症性疾病，其特征在于 异常愈合和肠狭窄在美国，超过50万患者患有克罗恩病及以上 每年新诊断出3万名患者。没有治愈性治疗方法。相反，目前的治疗集中在 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，靶向调节肠粘膜屏障和局部免疫信号， 肠道可以逆转疾病的发展调节免疫和粘膜愈合的一种有前途的方法是 利用由胃肠道中的肠道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。然而，除了一些初步数据显示， 这些分子保护小鼠免受急性肠道炎症，这些免疫调节剂的效用 治疗肠道炎症的分子仍不清楚。我们发明了一种新的分子， 这些细菌分子在腹膜内注射后显示出对肠道炎症的改善的保护作用， 注射在急性肠道炎症小鼠模型中。然而，目前还不清楚我们的分子是否可以 口服而不是注射。因此，在本项目的第一部分，我们将评估治疗 本发明分子在经历急性肠炎症的小鼠中口服给药后的效果。 其次，由于急性肠道炎症模型只能模拟疾病的某些方面， 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 我们的分子是否提供了一个有前途的治疗策略克罗恩病，通过检查我们的 分子在自发发育的慢性肠道疾病遗传小鼠模型中的治疗作用 炎症这种小鼠模型依赖于Mdr 1a基因中的工程遗传缺陷。MDR 1A发挥着 在调节肠粘膜的先天性和适应性免疫中的作用。基因失活后， mdr 1a，小鼠在8-14周龄时发生慢性肠道炎症， 发生在克罗恩病患者比化学诱导的急性模型。因此，Mdr 1a-/-中的阳性结果 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，我们希望确定我们的分子是否可以用于 口服以及它是否能保护小鼠免受更类似克罗恩病的慢性肠道炎症 疾病这些研究的结果对于确定药物开发过程的下一步至关重要， 我们的分子，这是旨在开发一种易于使用，肠道导向治疗克罗恩病。这 是重要的，因为目前克罗恩病的治疗选择显示出有限的疗效， （自我）注射。克罗恩病患者期待着新的和实用的，非免疫抑制药物。