Carbohydrate-based Therapy for Lung Disease

以碳水化合物为基础的肺部疾病治疗

• 批准号: 10225939
• 负责人: John V Fahy
• 金额: $ 76.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225939
• 关键词: Address; Adrenal Cortex Hormones; Agonist; Amino Acids; Anti-Cholinergics; Area; Asthma; Back; Carbohydrates; Characteristics; Chest; Cleaved cell; Clinic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Communication; Cysteine; Cystic Fibrosis; Cystic Fibrosis sputum; Data; Disease; Disulfides; Elasticity; Elements; Environmental Exposure; Evaluation; Formulation; Galactose; Gel; Goals; Hand; Health; Human; Image; Inflammation; Inhalators; Lead; Libraries; Lung; Lung diseases; Mucins; Mucolytics; Mucous body substance; Outcome; Oxidative Stress; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacy (field); Phase; Phenotype; Polymers; Population; Positioning Attribute; Powder dose form; Program Development; Property; Research; Respiratory physiology; Role; Safety; Subgroup; Sulfhydryl Compounds; Testing; Time; Toxic effect; Toxicology; Translating; Translations; Work; X-Ray Computed Tomography; asthmatic; base; chest computed tomography; clinical candidate; clinically relevant; college; cost; crosslink; cystic fibrosis patients; data integration; data management; design; disulfide bond; drug development; eosinophil; first-in-human; human subject; imaging biomarker; improved; lead optimization; mucus-associated lung diseases; multidisciplinary; neutrophil; novel; oxidant stress; oxidation; phase 1 study; practical application; pre-clinical; programs; recombinant human DNase; safety study; scaffold; treatment strategy

Project Summary The goal of this application is to translate our discovery of an unsuspected mechanism of mucus pathology into a mucolytic drug strategy that could benefit millions of patients with mucus-associated lung disease. Specifically, we have discovered that mucus elasticity in CF results from neutrophil oxidant stress that cross- links mucin polymers to stiffen the airway mucus gel. Because oxidative stress occurs in multiple situations associated with inflammation and environmental exposures, we hypothesize that oxidative stress is a ubiquitous and previously unsuspected cause of increases in mucus elasticity in disease. This provides rationale for developing mucolytic drugs with wide clinical utility that can cleave disulfide bonds as a mechanism of action. Our tPPG group has synthesized novel thiol-modified carbohydrate compounds (“thiol- saccharides”) and shown them to have potent mucolytic activity in CF sputum. We have encouraging preliminary data for their formulation as dry powders and reassuring data regarding their safety. We now propose three projects supported by two cores to bring a thiol-saccharide to the clinic as a new treatment for CF and other mucus-associated lung diseases. Project 1 will modify carbohydrate scaffolds to create a library of synthetic mucolytic compounds, conduct lead optimization studies, and formulate thiol-saccharides for delivery as dry powders. Project 2 will screen the mucolytic efficacy of thiol-saccharide library to aid in identification of lead compounds and the preclinical candidate compound and will identify a sub-population of asthmatics who may benefit from mucolytic treatment. Project 3 will progress the lead thiol-saccharides to a preclinical candidate and then to the clinic as a novel mucolytic strategy for mucus pathology in cystic fibrosis. Cores A and B will provide all three projects with support in areas of administration, finance, communication, data management and integration and human subjects. Our proposal is timely and highly clinically relevant, and it is supported by strong preliminary data and high promise for realizing our goal. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目摘要 该应用的目的是将我们发现的粘液病理学机制转化为 一种粘液溶剂策略，可以使数百万粘液相关肺部疾病患者受益。 具体而言，我们发现CF的粘液弹性是由中性粒细胞氧化应激引起的， 将粘蛋白聚合物连接以使气道粘液凝胶加强。因为氧化应激发生在多种情况下 与感染和环境暴露有关，我们假设氧化物应激是 无处不在的疾病粘液弹性增加的无处不在的原因。这提供了 开发具有广泛临床实用性的粘液溶剂的基本原理，可以将二硫键清除为一种 作用机理。我们的TPPG组合成了新型硫醇改性的碳氢化物化合物（“硫醇 - 糖”）并表明它们具有CF痰液中潜在的粘液溶液活性。我们很鼓励 其公式的初步数据作为干粉，并放心有关其安全性的数据。我们现在 提案三个核心支持的三个项目将硫醇 - 糖类带到诊所，以此作为新的治疗方法 CF和其他与粘液相关的肺部疾病。项目1将修改碳水化合物脚手架以创建图书馆 合成粘液溶解化合物，进行铅优化研究，并为硫代糖制成硫代糖 作为干粉末输送。项目2将筛选硫醇 - 糖库的粘液溶解效率以帮助 识别铅化合物和临床前候选化合物，将确定 哮喘患者可能会受益于脂肪疗法。项目3将把铅硫醇含糖推向 临床前候选者，然后到诊所作为囊性纤维化中粘液病理学的新型粘液溶解策略。 核心A和B将为所有三个项目提供管理，金融，沟通， 数据管理和整合和人类主题。我们的建议在临床上是及时且高度相关的， 强大的初步数据和实现我们的目标的高希望得到了支持。 PHS 398/2590（修订版06/09）页面延续格式页面

项目成果

A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.

• DOI: 10.1183/13993003.02022-2022
• 发表时间: 2023-05
• 期刊: The European respiratory journal

The Use of a Three-Fluid Atomising Nozzle in the Production of Spray-Dried Theophylline/Salbutamol Sulphate Powders Intended for Pulmonary Delivery.

• DOI: 10.3390/pharmaceutics12111116
• 发表时间: 2020-11-20
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Focaroli S;Jiang G;O'Connell P;Fahy JV;Healy AM
• 通讯作者: Healy AM

Erratum: COVID-19-related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids.

• DOI: 10.1164/rccm.v202erratum7
• 发表时间: 2020-12-15
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Peters MC;Fahy JV
• 通讯作者: Fahy JV

FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection.

• DOI: 10.1371/journal.ppat.1005555
• 发表时间: 2016-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Kerr SC;Fischer GJ;Sinha M;McCabe O;Palmer JM;Choera T;Lim FY;Wimmerova M;Carrington SD;Yuan S;Lowell CA;Oscarson S;Keller NP;Fahy JV
• 通讯作者: Fahy JV