Nitric oxide-releasing cystic fibrosis therapeutics

 描述(申请人提供)：囊性纤维化是一种遗传的限制生命的疾病，在美国影响3万人，在全球影响7万人。慢性支气管炎患者肺部粘液粘度的增加阻止了细菌通过正常方式(例如纤毛跳动和咳嗽)的清除，从而允许细菌的增殖和生物膜的形成。细菌生物被膜可降解肺部，是CF发病率和死亡率的主要原因。虽然基因疗法可能治愈CF，但有1800多种基因突变会导致CF，每一种突变都需要开发一种特定的药物。因此，在消除细菌生物被膜方面比目前治疗更有效的治疗方法的开发代表着一种更具成本效益和更及时的方法来延长CF患者的预期寿命。本项目的目标是开发能够释放内源性抗菌剂一氧化氮(NO)的水溶性壳聚糖支架，并有效地清除CF生物膜。这些新型不释放支架的有效性将在模拟CF肺的条件下针对与CF相关的细菌菌株进行测试。我们假设，减少NO的二硫化物反应性也将降低粘液粘度，潜在地增强后续NO治疗的作用，并提高先天免疫系统进一步控制肺部细菌水平的能力。因此，我们将系统地研究NO和NO释放支架成分对粘液粘度的影响，以确定NO作为一种双重作用的CF治疗的潜力。这些高分子支架代表了第一种适用于肺部给药的基于NO的疗法，因此具有很高的创新性。

 DESCRIPTION (provided by applicant): Cystic fibrosis is a genetically inherited life-limiting disorder that affects 30,000 people in the US and 70,000 people worldwide. Increased mucus viscosity in the lungs of CF-afflicted individuals prevents the clearance of bacteria via normal means (e.g., ciliary beating and coughing), thereby allowing proliferation and the formation of biofilms. Bacterial biofilms degrade the lungs and are the primary cause of CF morbidity and mortality. While gene therapies could potentially cure CF, there are over 1,800 genetic mutations which cause CF, each of which would require the development of a specific drug. Therefore, development of therapeutics that are more effective than current treatments at eliminating bacterial biofilms represents a more cost effective and timely approach to increasing the life expectancy of people with CF. The goal of this project is to develop water soluble chitosan scaffolds that release nitric oxide (NO), an endogenous antibacterial agent, and effectively eradicate CF biofilms. The efficacy of these novel NO-release scaffolds will be tested against CF-relevant bacteria strains in conditions that mimic the CF lung. We hypothesize that disulfide-reducing reactivity of NO will also reduce the mucus viscosity, potentially enhancing the action of subsequent NO treatments and improving the ability of the innate immune system to further control bacterial levels in the lungs. The effects of NO and NO-release scaffold composition on mucus viscosity will thus be systematically studied to determine NO's potential as a dual action CF therapeutic. These macromolecular scaffolds represent the first NO-based therapeutics suitable for pulmonary delivery, and are thus highly innovative.