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性心脏病的主要原因。它 表现为一种急性自限性疾病，伴有发烧以及皮肤和粘膜炎症。在 KD，由迄今为止未知的外在因素触发的免疫系统诱发多系统血管炎，包括 冠状动脉。即使遵循当前的治疗指南，30% 的川崎病儿童仍会患有冠心病 动脉扩张（CAD）。 CAD 患者可能面临永久性和潜在破坏性的并发症，例如 如冠状动脉病变、心肌梗塞甚至死亡。目前没有可用的治疗方法或 川崎病儿童的 CAD 预防。在川崎病急性期，巨噬细胞和淋巴细胞被激活 冠状动脉壁诱导产生负责弹性蛋白的基质金属蛋白酶 9 (MMP-9) 降解导致 CAD 和动脉瘤。多西环素（一种常见抗生素和已知的 MMP-9 抑制剂） 被证明可以减少 MMP-9 介导的冠状动脉弹性蛋白分解并改善冠状动脉结局 KD 动物模型。多西环素给药也被证明可以降低主动脉中 MMP-9 的活性 患有腹主动脉瘤的成人的壁。我们的初步和公布的数据表明，亲 MMP-9 是一种敏感的生物标志物，可在 CAD 时检测儿童 KD 急性期的炎症 发生，强力霉素可以预防川崎病儿童 CAD 的进展。根据这些数据，我们将 检验以下两个假设：1）在川崎病急性期给儿童服用多西环素会 降低 MMP-9 的循环水平； 2) 川崎病急性期使用多西环素治疗是安全的 并能有效预防儿童冠心病的进展和动脉瘤的形成。 具体目标 1：表征循环 pro-MMP-9 和 MMP-9 水平响应 3- 川崎病急性期儿童每周口服多西环素，通过定量亲 3周前和3周后儿童血清样本中的MMP-9和MMP-9水平（通过ELISA测量） 多西环素治疗过程，并比较急性川崎病儿童和非川崎病儿童与对照组的变化 强力霉素治疗。具体目标 2：评估 3- 冠状动脉直径的变化 川崎病急性期儿童每周口服多西环素，通过评估 在 KD 急性期的 4 个时间点使用既定的超声心动图标准检查冠状动脉 并与未接受多西环素治疗的急性川崎病儿童的对照进行比较。根据本次的结果 试点研究，我们将开展一项前瞻性、多中心、盲法对照临床试验来评估疗效 强力霉素治疗预防 CAD 和动脉瘤。如果多西环素被证明是有益的，我们将 建议改变目前接受的川崎病儿童治疗方案，将多西环素用于治疗 预防冠状动脉瘤和潜在致命的并发症。