Anti-inflammatory Nicotinic Agonists for Therapy of Ulcerative Colitis

用于治疗溃疡性结肠炎的抗炎烟碱激动剂

基本信息

批准号：
7910771
负责人：
SUSAN C WRIGHT
金额：
$ 50.16万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910771
关键词：
Acetylcholine Adverse effects Animal Model Anti-Inflammatory Agents Anti-inflammatory Back Binding Biological Response Modifier Therapy Chemicals Chronic Colitis Colon Development Disease Drug Formulations Future GTS-21 Goals Histopathology Human Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Response Lead Modeling Monitor Mucous Membrane Mus Nervous system structure Nicotinic Agonists Nicotinic Receptors Oral Administration Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Preparation Production Reflux Safety Symptoms Testing Therapeutic Tissues Treatment Efficacy Ulcerative Colitis United States Food and Drug Administration Vagus nerve structure Work acetylcholine receptor agonist analog base conventional therapy cytokine cytokine therapy design drug candidate drug efficacy in vivo macrophage mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics phase 1 study pre-clinical public health relevance

项目摘要

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic tissue-destructive disease in which cellular inflammation and inflammatory cytokines ultimately lead to damage of the colonic mucosa. There is no effective cure, and while standard therapies can ameliorate symptoms in some patients, they are not effective in a significant number of patients and can also cause severe side effects. Consequently, new therapeutic approaches are needed to inhibit the inappropriate and exaggerated inflammatory response in UC patients. The new therapeutic target that this application will develop is based on the recent elucidation of the "inflammatory reflux" in which the nervous system through the vagus nerve regulates immune responses by release of acetylcholine which binds to macrophage 17 nicotinic acetylcholine receptors (nAChR) resulting in inhibition of inflammatory cytokine production. The results of Phase I studies demonstrated proof of principle that the17 nicotinic acetylcholine receptor agonist (GTS-21) ameliorates disease symptoms and tissue damage in two mouse models of UC. The goal of this Phase II proposal is to further advance preclinical development of GTS-21. The drug will be evaluated in vivo for its ability to ameliorate development of disease symptoms and colon pathological changes in two models of murine colitis, which resemble human UC. Drugs will be tested alone and combined with conventional UC therapies at either the initiation of colitis or after the development of symptoms. Drug efficacy will be monitored by disease symptoms, histopathology of the colon, and production of inflammatory mediators. We will also prepare and test a formulation of GTS-21 designed for selective delivery to the colon after oral administration. These studies will provide the groundwork for preparation of an IND and future Phase 2 clinical trials. Because GTS-21 will inhibit production of multiple inflammatory cytokines (as shown in Phase I studies) known to be responsible, at least in part, for damage to colonic mucosa, this therapeutic approach should be more effective than other biological therapies that target only one cytokine. Ultimately this work will develop a new therapeutic option for UC patients that is based on a novel anti-inflammatory pathway. GTS-21 may be superior to current treatments and offer a new option for patients unresponsive to conventional therapies. PUBLIC HEALTH RELEVANCE: This project will develop a new drug that will suppress production of multiple inflammatory cytokines for the therapy of patients with ulcerative colitis. It has the potential to benefit patients unresponsive to conventional therapies.

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性组织破坏性疾病，其中细胞炎症和炎性细胞因子最终导致结肠粘膜损伤。目前尚无有效的治愈方法，虽然标准疗法可以改善某些患者的症状，但对相当数量的患者无效，并且还会引起严重的副作用。因此，需要新的治疗方法来抑制 UC 患者不适当和过度的炎症反应。该应用将开发的新治疗靶点基于最近对“炎症反流”的阐明，其中神经系统通过迷走神经释放乙酰胆碱来调节免疫反应，乙酰胆碱与巨噬细胞 17 烟碱乙酰胆碱受体 (nAChR) 结合，导致抑制炎症细胞因子的产生。 I 期研究的结果证明了 17 烟碱乙酰胆碱受体激动剂 (GTS-21) 可改善两种 UC 小鼠模型的疾病症状和组织损伤。该二期提案的目标是进一步推进 GTS-21 的临床前开发。该药物将在两种类似于人类溃疡性结肠炎的小鼠结肠炎模型中进行体内评估，评估其改善疾病症状和结肠病理变化的能力。在结肠炎开始时或出现症状后，药物将单独进行测试，并与传统的溃疡性结肠炎疗法相结合。药物疗效将通过疾病症状、结肠组织病理学和炎症介质的产生来监测。我们还将制备并测试一种 GTS-21 制剂，该制剂设计用于口服给药后选择性递送至结肠。这些研究将为 IND 和未来 2 期临床试验的准备奠定基础。由于 GTS-21 将抑制已知至少部分导致结肠粘膜损伤的多种炎症细胞因子的产生（如 I 期研究所示），因此这种治疗方法应该比其他仅针对一种细胞因子的生物疗法更有效细胞因子。最终，这项工作将为 UC 患者开发一种基于新型抗炎途径的新治疗方案。 GTS-21可能优于目前的治疗方法，并为对传统疗法无反应的患者提供新的选择。公共健康相关性：该项目将开发一种新药，可抑制多种炎症细胞因子的产生，用于治疗溃疡性结肠炎患者。它有可能使对传统疗法无反应的患者受益。