MMP9 as a response identification biomarker for doxycycline in Kawasaki disease

MMP9 作为川崎病强力霉素反应识别生物标志物

• 批准号: 9184279
• 负责人: ANDRAS BRATINCSAK
• 金额: $ 7.94万
• 依托单位: KAPIOLANI MEDICAL CENTER WOMEN/CHILDREN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-22 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9184279
• 关键词: Abdominal Aortic Aneurysm; Acute; Adult; Age; Aneurysm; Animal Model; Animals; Antibiotics; Aortic Aneurysm; Biological; Biological Markers; Blinded; Blood Vessels; Caliber; Categories; Cessation of life; Child; Clinical; Clinical Research; Complication; Controlled Clinical Trials; Coronary; Coronary Aneurysm; Coronary Arteriosclerosis; Coronary artery; Data; Disease; Doxycycline; Echocardiography; Elastin; Enzyme-Linked Immunosorbent Assay; Face; Fever; Gelatinase B; Gender; Goals; Guidelines; Heart Diseases; High Prevalence; Immune system; Incidence; Inflammation; Investigational Drugs; Lymphocyte; MMP9 gene; Measures; Mediating; Medical; Mucocutaneous Lymph Node Syndrome; Mucous Membrane; Myocardial Infarction; New Drug Approvals; Oral Administration; Outcome; Patients; Phase; Pilot Projects; Prevention; ProMMP-9; Protocols documentation; Publishing; Randomized Clinical Trials; Sampling; Serum; Skin; Testing; Therapeutic; Time; Tissues; Treatment Protocols; United States; Vascular Diseases; Vasculitis; animal data; base; biomarker identification; clinical effect; disorder prevention; experience; extracellular; improved; improved outcome; inhibitor/antagonist; innovation; macrophage; mouse model; prevent; prospective; research study; response; standard care; stem

ABSTRACT Kawasaki disease (KD) is the leading cause of acquired heart disease in children of the developed world. It presents as an acute self-limiting illness with fever and inflammation of the skin and mucous membranes. In KD, the immune system triggered by a so far unknown extrinsic factor induces multisystem vasculitis including the coronary arteries. Even following current therapeutic guidelines, 30% of children with KD will have coronary artery dilation (CAD). Patients with CAD may face permanent and potentially devastating complications, such as coronary vasculopathy, myocardial infarction and even death. Currently there is no available treatment or prevention of CAD in children with KD. In the acute phase of KD, activated macrophages and lymphocytes in the wall of the coronary arteries induce matrix metalloproteinase 9 (MMP-9) that is responsible for elastin degradation causing CAD and aneurysm. Doxycycline (a common antibiotic and a known inhibitor of MMP-9) was shown to decrease MMP-9-mediated coronary elastin breakdown and improve coronary outcome in animal models of KD. Doxycycline administration was also demonstrated to reduce MMP-9 activity in the aortic wall of adults with abdominal aortic aneurysm. Our preliminary and published data demonstrates that pro- MMP-9 is a sensitive biomarker to detect inflammation in children during the acute phase of KD when CAD occurs, and doxycycline may prevent the progression of CAD in children with KD. Based on these data, we will test the following two hypotheses: 1) doxycycline administration in children during the acute phase of KD will decrease the circulating level of MMP-9; and 2) doxycycline treatment during the acute phase of KD is safe and effective to prevent the progression of CAD and aneurysm formation in children. Specific aim 1: To characterize the change in circulating pro-MMP-9 and MMP-9 levels in response to a 3- week oral administration of doxycycline in children during the acute phase of KD, by the quantification of pro- MMP-9 and MMP-9 levels (measured by ELISA) in serum samples of children before and after a 3-week course of doxycycline treatment, and comparing the changes to controls of children with acute KD and no doxycycline treatment. Specific aim 2: To assess the change in coronary artery diameter in response to a 3- week oral administration of doxycycline in children during the acute phase of KD, by assessing the size of coronary arteries using established echocardiographic standards during 4 time-points in the acute phase of KD and comparing to controls of children with acute KD and no doxycycline treatment. Based on the results of this pilot study, we will develop a prospective, multi-center, blinded controlled clinical trial to assess the efficacy of doxycycline treatment in the prevention of CAD and aneurysm. If doxycycline proves to be beneficial, we will propose a change of the currently accepted treatment protocol of children with KD to include doxycycline for the prevention of coronary artery aneurysms and potentially fatal complications.

抽象的 川崎病（KD）是发达国家儿童获得心脏病的主要原因。它 表现为一种急性自限性疾病，发烧，皮肤和粘膜发炎。在 KD，由迄今未知的外部因素触发的免疫系统诱导多系统血管炎，包括 冠状动脉。即使遵循当前的治疗指南，有30％的KD儿童将具有冠状动脉 动脉扩张（CAD）。 CAD患者可能面临永久性且可能毁灭性的并发症，此类并发症 作为冠状动脉病变，心肌梗塞甚至死亡。目前没有可用的治疗或 预防KD儿童的CAD。在KD的急性阶段，激活的巨噬细胞和淋巴细胞在 冠状动脉的壁诱导弹性弹性蛋白的基质金属蛋白酶9（MMP-9） 降解引起CAD和动脉瘤。强力霉素（一种常见的抗生素和已知的MMP-9抑制剂） 被证明可以降低MMP-9介导的冠状动脉脱落并改善冠状动脉结果 KD的动物模型。还证明了强力霉素给药可降低主动脉中的MMP-9活性 腹主动脉瘤的成年人墙。我们的初步和发布的数据表明， MMP-9是一种敏感的生物标志物，可在KD的急性阶段检测儿童的炎症 发生，强力霉素可能会阻止KD儿童的CAD进展。基于这些数据，我们将 测试以下两个假设：1）在KD急性阶段，儿童的多西环素给药 降低MMP-9的循环水平； 2）KD急性期的强力霉素治疗是安全的 有效地防止儿童CAD和动脉瘤形成的进展。 特定目标1：表征响应3-的循环Pro-MMP-9和MMP-9水平的变化 在KD的急性阶段，每周口服致力霉素，通过定量 MMP-9和MMP-9水平（通过ELISA测量）在3周之前和之后的儿童血清样品中 强力霉素治疗的过程，并将变化与急性KD儿童的控制和无 强力霉素治疗。特定目的2：评估响应3-的冠状动脉直径的变化 在KD急性阶段，一周的口服儿童的强力霉素，通过评估的大小 在KD的急性阶段，使用已建立的超声心动图标准的冠状动脉使用冠状动脉 并与患有急性KD儿童和无强力霉素治疗的儿童对照进行比较。基于此结果 试点研究，我们将开发一项预期的，多中心的，盲目的对照临床试验，以评估 强力霉素治疗预防CAD和动脉瘤。如果强力霉素被证明是有益的，我们将 建议更改KD儿童当前接受的治疗方案，包括 预防冠状动脉瘤和潜在的致命并发症。