UAB CF Research and Translation Core Center

需要新的疗法来治疗慢性阻塞性肺疾病（COPD）， 每年的医疗费用超过400亿美元，是第三大死亡原因。 在美国，也是健康差距的主要来源，在南方腹地的比例过高。 与囊性纤维化（CF）一样，COPD的特征是粘液阻塞， 加速肺功能丧失和死亡率过高。香烟烟雾呈现出各种各样的 体外和体内对气道上皮功能的有害影响以及我们的初步数据 表明它也会导致CFTR活性的显著降低，从而导致明显的 粘液纤毛运输减少。此外，CFTR功能障碍独立地与 慢性支气管炎和呼吸困难，即使戒烟也会持续存在， 在体外和体内通过激活野生型CFTR被CFTR增效剂ivacaftor逆转， 导致粘膜纤毛运输的强烈增加。结合前所未有的临床 通过增强粘膜纤毛清除在具有反应性的CF患者中观察到的改善 CFTR突变，这些数据表明CFTR代表了用依伐卡托处理的可行的CFTR突变。 治疗目标是解决慢性支气管炎COPD患者的粘液淤滞（可能 仅在美国就有超过800万患者）。在这个项目中，我们将调查 依伐卡托可以增加表现出以下症状COPD个体的CFTR活性的假设 慢性支气管炎虽然我们的初步数据令人信服，但关于最重要的问题 信息和反应终点和剂量选择要求本研究中概述的研究 应用程序.为了解决这个问题，我们设计了一个创新的2期，随机，双， 确定依伐卡托（VX-770）安全性和有效性的盲法、安慰剂对照初步试验 治疗慢性阻塞性肺疾病（多中心TOPIC研究）， 并将解决COPD和气道上皮生物学领域的一些关键问题 使用最新的方法来评估CFTR活性、上皮功能、粘膜纤毛清除， 临床结果。TOPIC研究将测试MCC是否可以在COPD中增加 慢性支气管炎患者，改善人类疾病，即使在没有先天性 CFTR基因突变。该试验将提供初步的概念验证， CFTR增效剂在COPD中的疗效，我们还将根据 种族/民族、社会经济状况和吸烟状况。如果成功的话， 建立一种新的治疗模式来解决COPD中的粘液功能障碍， 与死亡率和疾病进展独立相关的发病原因。

New therapies are needed for the treatment of chronic obstructive pulmonary disease (COPD), which accounts for over $40 billion in annual healthcare costs, is the 3rd leading cause of death in the U.S., and is major source of health disparity, being over-represented in the Deep South. Like cystic fibrosis (CF), COPD is characterized by mucus obstruction that is associated with accelerated loss of lung function and excess mortality. Cigarette smoke exhibits a variety of deleterious effects on airway epithelial function in vitro and in vivo and our preliminary data indicates it also causes a significant reduction in CFTR activity that leads to a pronounced decrement in mucociliary transport. Furthermore, CFTR dysfunction is independently associated with chronic bronchitis and dyspnea, can persist despite smoking cessation, and can be reversed by the CFTR potentiator ivacaftor in vitro and in vivo by activating wild-type CFTR, resulting in a robust increase in mucociliary transport. Combined with unprecedented clinical improvement via augmented mucociliary clearance observed in CF patients with a responsive CFTR mutation treated with ivacaftor, these data indicate that CFTR represents a viable therapeutic target to address mucus stasis in COPD patients with chronic bronchitis (potentially representing over 8 million patients in the U.S. alone). In this project, we will investigate the hypothesis that ivacaftor can augment CFTR activity in individuals with COPD who exhibit chronic bronchitis. Though our preliminary data are compelling, questions regarding the most informative and responsive endpoints and dose selection mandate the studies outlined in this application. To address this, we have designed an innovative Phase 2, Randomized, Double- blind, Placebo Controlled Pilot Trial to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease (The Multicenter TOPIC study), and will address a number of key questions to the field of COPD and airway epithelial biology using the latest methods for assessing CFTR activity, epithelial function, mucociliary clearance, and clinical outcomes. The TOPIC study will test whether MCC can be augmented in COPD patients with chronic bronchitis, ameliorating human disease even in the absence of congenital mutations in the CFTR gene. The trial will provide an initial proof of concept evaluating the efficacy of CFTR potentiators in COPD, and we will also examine differential effects based on race/ethnicity, socio-economic status, and smoking status. If successful, the results could establish a novel treatment paradigm to address mucus dysfunction in COPD, an important cause of morbidity that is independently associated with mortality and disease progression.