Carbohydrate-based Therapy for Lung Disease

项目摘要 这个应用程序的目标是将我们发现的粘液病理机制转化为 一种粘液溶解药物策略，可能使数百万粘液相关肺部疾病患者受益。 具体地说，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，这种应激交叉- 连接粘蛋白聚合物，使呼吸道粘液凝胶变硬。因为氧化应激发生在多种情况下 与炎症和环境暴露有关，我们假设氧化应激是一种 疾病中粘液弹性增加的无处不在的和以前未被发现的原因。这提供了 开发具有广泛临床用途的粘液溶解药物的理论基础，该药物可以作为一种 作用机制。我们的tPPG小组合成了新型的硫醇修饰的碳水化合物(“硫醇- 糖“)，并表明它们在CF痰中具有很强的粘液溶解活性。我们有鼓舞人心的 关于它们作为干粉配方的初步数据和关于它们安全性的令人放心的数据。我们现在 提出三个由两个核心支持的项目，将硫醇糖类作为一种新的治疗方法引入临床 Cf和其他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 对合成的粘液溶解化合物进行先导优化研究，并为 以干粉的形式交付。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 可能从粘液溶解治疗中受益的哮喘患者。项目3将使硫代糖铅的研究进展到 临床前候选，然后进入临床，作为囊性纤维化粘液病理的一种新的粘液溶解策略。 核心A和B将向所有三个项目提供行政、财务、通信、 数据管理和集成以及人类主体。我们的建议是及时的，具有高度的临床意义， 它得到了强劲的初步数据和实现我们目标的高度承诺的支持。 PHS 398/2590(06/09版)页面续格式页面

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