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

项目 3：用新型粘液溶解剂治疗 CF 中的粘膜淤积和气道阻塞

• 批准号: 9356820
• 负责人: SCOTT H DONALDSON
• 金额: $ 27.21万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356820
• 关键词: Abnormal ion transport; Adverse event; Affect; Agar Gel Electrophoresis; Asthma; Biological Assay; Biological Markers; Breathing; Bronchiectasis; Cessation of life; Chelating Agents; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Collection; Cross-Over Studies; Cysteine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Data; Dehydration; Detergents; Development; Disease; Disease model; Dose; Drug Kinetics; Exhalation; Frequencies; Gel; Goals; Health; Healthcare; Hydration status; Impairment; In Vitro; Ion Transport; Laboratories; Lead; Lung; Lung diseases; Magnetic Resonance Imaging; Measurement; Measures; Modality; Molecular; Monitor; Morbidity - disease rate; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Obstruction; Obstructive Lung Diseases; Outcome Measure; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Process; Property; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Radionuclide Imaging; Randomized; Reducing Agents; Reporting; Research; Respiratory physiology; Safety; Saline; Science; Severities; Sputum; Sulfhydryl Compounds; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Agents; Western Blotting; airway obstruction; base; cystic fibrosis airway; cystic fibrosis patients; disability; disulfide bond; extracellular; healthy volunteer; human disease; improved; indexing; mortality; novel; novel therapeutics; premature; pulmonary function; recombinant human DNase; safety testing; surfactant; targeted agent; therapy development

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.

项目摘要 粘液性气道阻塞是CF肺病的重要病理特征。现有治疗 仅部分有效缓解该阻塞，并且需要额外的治疗。凝胶形成粘蛋白 分子是CF粘液的主要成分，并在很大程度上决定其生物流变学性质。 以粘蛋白分子为靶点改善气道转运的吸入剂的研究进展 粘液是合理的和有吸引力的治疗目标。在这个项目中，我们建议首先测试一本小说的安全性， 在单次剂量递增研究中，CF受试者吸入粘液溶解剂。然后我们将评估这种能力， 在安慰剂中，在两周的使用期间改善粘液清除和减少气道阻塞的药剂 CF的对照交叉研究。将使用相关的、新的结局指标来评价药物作用 对粘液清除（γ射线照相术）和气道阻塞（19 F-MRI和1H-MRI/UTE）的影响，此外， 传统临床试验终点。这些功能和结构模式的结合， 提高我们对这种异质性肺部疾病的药物作用的理解。