Carbohydrate-based Therapy for Lung Disease

以碳水化合物为基础的肺部疾病治疗

基本信息

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
项目类别：
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

项目摘要

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

项目概要该应用的目标是将我们对粘液病理学机制的发现转化为一种粘液溶解药物策略，可以使数百万患有粘液相关肺部疾病的患者受益。具体来说，我们发现 CF 中的粘液弹性是由中性粒细胞氧化应激引起的，该应激会交叉连接粘蛋白聚合物以硬化气道粘液凝胶，因为氧化应激在多种情况下都会发生。与炎症和环境暴露有关，我们勇敢地承认氧化应激是一种疾病中粘液弹性增加的普遍存在且以前未被怀疑的原因。开发具有广泛临床用途的粘液溶解药物的基本原理，该药物可以裂解二硫键作为我们的 tPPG 小组合成了新型硫醇修饰的碳水化合物化合物（“硫醇-”）。糖”），并显示它们对 CF 痰具有有效的粘液溶解活性。我们现在获得了其干粉配方的初步数据以及有关其安全性的可靠数据。由两个核心支持的三个项目将硫醇糖作为一种新的治疗方法引入临床 CF 和其他与粘液相关的肺部疾病项目 1 将修改碳水化合物支架以创建一个库。合成粘液溶解化合物，进行先导化合物优化研究，并配制硫醇糖项目 2 将筛选硫醇糖库的粘液溶解功效以帮助鉴定先导化合物和临床前候选化合物，并将鉴定一个亚群可能受益于粘液溶解治疗的哮喘患者项目 3 将把铅硫醇糖发展为一种药物。临床前候选者，然后作为囊性纤维化粘液病理学的新型粘液溶解策略进入临床。核心 A 和 B 将为所有三个项目提供行政、财务、沟通、我们的建议是及时且高度临床相关的。它得到了强有力的初步数据和实现我们目标的巨大承诺的支持。 PHS 398/2590（修订版 06/09）页面延续格式页面

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

一种新型硫醇糖粘液溶解剂，用于治疗粘液阻塞性肺部疾病。

DOI：
发表时间：
2023-05
期刊：
影响因子：
0
作者：
Addante, Annalisa;Raymond, Wilfred;Gitlin, Irina;Charbit, Annabelle;Orain, Xavier;Scheffler, Aaron Wolfe;Kuppe, Aditi;Duerr, Julia;Daniltchenko, Maria;Drescher, Marika;Graeber, Simon Y;Healy, Anne;Oscarson, Stefan;Fahy, John V;Mall, Ma
通讯作者：
Mall, Ma

A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery.

一种实验设计 (DoE) 方法，用于优化喷雾干燥工艺条件，用于生产海藻糖/亮氨酸制剂并应用于肺部输送。

DOI：
发表时间：
2019-05-01
期刊：
影响因子：
0
作者：
Focaroli, S;Mah, P T;Hastedt, J E;Gitlin, I;Oscarson, S;Fahy, J V;Healy, A M
通讯作者：
Healy, A M

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

烟曲霉中的 FleA 表达可被粘蛋白和巨噬细胞上的岩藻糖基化结构识别，从而预防肺部感染。

DOI：
发表时间：
2016-04
期刊：
影响因子：
6.7
作者：
Kerr, Sheena C;Fischer, Gregory J;Sinha, Meenal;McCabe, Orla;Palmer, Jonathan M;Choera, Tsokyi;Lim, Fang Yun;Wimmerova, Michaela;Carrington, Stephen D;Yuan, Shaopeng;Lowell, Clifford A;Oscarson, Stefan;Keller, Nancy P;Fahy, John V
通讯作者：
Fahy, John V

After asthma: redefining airways diseases.

继哮喘之后：重新定义呼吸道疾病。

DOI：
发表时间：
2018-01-27
期刊：
影响因子：
0
作者：
Pavord, Ian D;Beasley, Richard;Agusti, Alvar;Anderson, Gary P;Bel, Elisabeth;Brusselle, Guy;Cullinan, Paul;Custovic, Adnan;Ducharme, Francine M;Fahy, John V;Frey, Urs;Gibson, Peter;Heaney, Liam G;Holt, Patrick G;Humbert, Marc;Lloyd, Clare M
通讯作者：
Lloyd, Clare M

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

使用三流体雾化喷嘴生产用于肺部输送的喷雾干燥茶碱/硫酸沙丁胺醇粉末。