Project 3: Treatment of mucostasis and airways obstruction in CF with a novel mucolytic

项目总结 黏液阻塞是慢性阻塞性肺疾病的重要病理特征。可用的治疗方法有 在缓解这种梗阻方面只有部分有效，需要额外的治疗。凝胶性粘蛋白 分子是碳纤维粘液的主要成分，在很大程度上决定了其生物流变性。 靶向粘蛋白分子和改善呼吸道运输能力的吸入剂的发展 粘液是一种合理而有吸引力的治疗目标。在这个项目中，我们建议首先测试一部小说的安全性 单次递增剂量研究中吸入性粘液在CF受试者中的应用。然后我们将评估这一能力 安慰剂在使用两周内改善粘液清除和减少呼吸道阻塞的药物 慢性阻塞性肺疾病对照交叉研究将利用相关的、新的结果衡量标准来评估药物效果 粘液清除(伽马核素扫描)和呼吸道阻塞(19F-MRI，1H-MRI/UTE)，除了 传统的临床试验终点。这些功能和结构形式的结合应该大大 提高我们对药物对这种异质性肺部疾病的影响的了解。

PROJECT SUMMARY Mucus obstruction of airways is a significant pathologic feature of CF lung disease. Available therapies are only partially effective at relieving this obstruction, and additional treatments are needed. Gel-forming mucin molecules are a major constituent of CF mucus and to a large degree determines its bio-rheological properties. The development of inhaled agents that target mucin molecules and improve the transportability of airway mucus is a rational and attractive therapeutic goal. In this Project, we propose to first test the safety of a novel inhaled mucolytic in CF subjects in a single ascending dose study. We will then evaluate the ability of this agent to improve mucus clearance and reduce airways obstruction during two weeks of use, in a placebo controlled cross-over study in CF. Relevant, novel outcome measures will be utilized to evaluate drug effects on mucus clearance (gamma scintigraphy) and airways obstruction (19F-MRI with 1H-MRI/UTE), in addition to traditional clinical trial endpoints. The combination of these functional and structural modalities should greatly enhance our understanding of drug effects on this heterogeneous lung disease.