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.

项目概要克罗恩病是一种使人衰弱的胃肠道慢性炎症性疾病，其特征是在美国，超过 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，目前尚无有效治疗方法。迫切需要新的治疗方法来控制症状和减少新的发作。我们着迷于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进展，调节免疫和粘膜愈合的一种有前途的方法是。利用胃肠道共生细菌释放的分子作为免疫系统然而，除了一些初步数据显示之外，我们还进化出了与这些分子相互作用的特定方式。这些分子可以保护小鼠免受急性肠道炎症，这些免疫调节剂的用途治疗肠道炎症的分子仍不清楚。我们开发了一种新分子，其灵感来自于。这些细菌分子在腹膜内注射后表现出更好的针对肠道炎症的保护作用然而，我们的分子是否可以注射到急性肠道炎症模型中尚不清楚。口服而不是注射给药因此，在该项目的第一部分中，我们将评估治疗效果。我们的分子对经历急性肠道炎症的小鼠口服给药的影响。其次，由于肠道炎症的急性模型只能模拟疾病的某些方面，并且无法捕获在克罗恩病中观察到的多方面、慢性、进行性炎症，我们将进一步验证通过检查我们的分子是否为克罗恩病提供了有前途的治疗策略分子在自发发育的慢性肠道遗传小鼠模型中的作用该小鼠模型依赖于 Mdr1a 基因的工程遗传缺陷。基因失活后在调节肠粘膜先天性和适应性免疫中的作用。 Mdr1a，小鼠在 8-14 周龄时出现慢性肠道炎症，更类似于与化学诱导的急性模型相比，这种情况在克罗恩病患者中发生，因此，Mdr1a-/- 出现阳性结果。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。在完成这些研究后，我们希望确定我们的分子是否可以使用口服，以及它是否可以保护小鼠免受更类似于克罗恩病的慢性肠道炎症的影响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。我们的分子旨在开发一种易于使用的肠道定向疗法来治疗克罗恩病。很重要，因为当前克罗恩病的治疗方案显示出有限的疗效并且通常需要（自我）注射克罗恩病患者期待新的、实用的、非免疫抑制药物。