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

基本信息

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
项目类别：
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&apos 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

项目摘要

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胃肠道的一种使人衰弱和慢性炎症性疾病，其特征是异常的愈合和肠道狭窄。在美国，> 500,000名患者患有克罗恩病及以上每年新诊断出30,000名患者。不存在现代治疗。相反，当前的治疗重点在管理符号并减少新情节的发生时。迫切需要新的治疗方法。我们假设针对肠粘膜屏障和局部免疫信号的靶向调节肠道可以逆转疾病的进展。调节免疫力和粘膜愈合的一种承诺方法是利用共生细菌在胃肠道中释放的分子作为免疫系统已经进化了与这些分子相互作用的特定方法。但是，除了一些显示的初步数据外这样的分子可以预防小鼠的急性肠注射，这些免疫调节的效用治疗肠道感染的分子尚不清楚。我们开发了一个新分子，灵感来自这些细菌分子在腹膜内表现出改善防止肠道注射的保护在肠道注射的急性小鼠模型中注射。但是，目前尚不清楚我们的分子是否可以口服而不是注射。在本项目的第一部分中，我们将评估该疗法我们分子对急性肠注射的小鼠口服给药的影响。接下来，作为肠道注射的急性模型，仅模仿疾病的某些方面而无法捕获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通过检查我们的克罗恩氏病提供了有希望的治疗策略分子在赞助的慢性肠模型中的治疗作用炎。该小鼠模型依赖于MDR1A基因中的工程遗传缺陷。 MDR1A播放a 在肠道粘膜中先天和适应性免疫的调节中的作用。遗传失活 MDR1A，小鼠在8-14周龄时出现慢性肠注射，与什么相似比化学诱导的急性模型发生在克罗恩病患者中。这是在此mdr1a - / - 的积极结果小鼠模型将为我们的分子治疗克罗恩病的效用提供进一步的验证。完成这些研究时，我们希望确定是否可以使用分子口服以及它是否可以保护小鼠免受慢性肠注射的侵害，更像克罗恩疾病。这些研究的结果对于定义药物开发过程的下一步至关重要我们的分子旨在为克罗恩病开发一种易于使用的肠道疗法。这很重要，因为克罗恩病的当前治疗选择表现出有限的效率，并且经常需要（自我） - 注入。克罗恩（Crohn）的患者期待新的，实用的非免疫抑制药物。