UAB CF Research and Translation Core Center

UAB CF 研究与翻译核心中心

• 批准号: 9901116
• 负责人: MARK T DRANSFIELD
• 金额: $ 84.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901116
• 关键词: Address; Area; Biological Markers; Biology; Bronchitis; Cause of Death; Characteristics; Chemosensitization; Chlorides; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Cotinine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Deep South; Disease Progression; Dose; Double-Blind Method; Dyspnea; Education; Enrollment; Epithelial; Ethnic Origin; Excess Mortality; Exhibits; Fibrinogen; Financial Hardship; Functional disorder; Funding; Future; Goals; Grant; Health Care Costs; Hydration status; Image; Impairment; In Vitro; Incidence; Income; Individual; Intervention; Intestines; Laboratories; Measures; Methods; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mutation; Obstruction; Optical Coherence Tomography; Outcome; Outcome Assessment; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Placebos; Production; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Race; Randomized; Regulator Genes; Research; Research Personnel; Resolution; Respiratory Signs and Symptoms; Respiratory physiology; Safety; Severity of illness; Smoke; Smoking; Smoking Status; Social support; Socioeconomic Factors; Socioeconomic Status; Solid; Source; Sweat; Sweat Glands; Symptoms; Target Populations; Testing; Tobacco smoke; Translations; United States National Institutes of Health; VX-770; base; cigarette smoke; cigarette smoking; cystic fibrosis patients; design; double-blind placebo controlled trial; drug mechanism; health disparity; human disease; imaging modality; improved; in vivo; in vivo imaging; innovation; low socioeconomic status; mortality; novel; novel therapeutics; operation; pilot trial; pre-clinical; ranpirnase; respiratory; response; smoking cessation; therapeutic target; treatment effect; treatment response; trend; urinary

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.

慢性阻塞性肺疾病（COPD）的治疗需要新的疗法，