Anti-inflammatory Nicotinic Agonists for Therapy of Ulcerative Colitis

描述(申请人提供)：溃疡性结肠炎(UC)是一种慢性组织破坏性疾病，其细胞炎症和炎性细胞因子最终导致结肠粘膜损伤。目前还没有有效的治疗方法，虽然标准疗法可以改善一些患者的症状，但对相当数量的患者无效，还可能导致严重的副作用。因此，需要新的治疗方法来抑制UC患者不适当和夸张的炎症反应。这一应用将开发的新的治疗靶点是基于最近阐明的“炎性反流”，其中神经系统通过迷走神经释放乙酰胆碱，通过与巨噬细胞17烟碱型乙酰胆碱受体(NAChR)结合来调节免疫反应，从而抑制炎性细胞因子的产生。第一阶段研究的结果证明了烟碱型乙酰胆碱受体激动剂(GTS-21)可以改善两种UC小鼠模型的疾病症状和组织损伤。这一第二阶段提案的目标是进一步推进GTS-21的临床前开发。该药物将在体内评估其改善两种类似人类UC的小鼠结肠炎模型的疾病症状和结肠病理变化的能力。药物将在结肠炎开始时或症状出现后单独进行测试，并与传统的UC治疗相结合。药物疗效将通过疾病症状、结肠组织病理学和炎性介质的产生来监测。我们还将准备和测试GTS-21的配方，该配方设计用于口服给药后选择性地给药到结肠。这些研究将为IND和未来的第二阶段临床试验的准备工作奠定基础。由于GTS-21将抑制多种炎性细胞因子的产生(如I期研究所示)，已知的多种炎性细胞因子至少在一定程度上对结肠粘膜的损害负有责任，因此这种治疗方法应该比其他只针对一种细胞因子的生物疗法更有效。最终，这项工作将为UC患者开发一种基于新的抗炎途径的新的治疗方案。GTS-21可能优于目前的治疗方法，并为对传统治疗无效的患者提供了一种新的选择。 公共卫生意义：该项目将开发一种新药，用于治疗溃疡性结肠炎患者，抑制多种炎性细胞因子的产生。它有可能使对传统疗法无效的患者受益。

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.