Mucolytic for enhanced mucus and biofilm clearance in cystic fibrosis patients

描述（由申请人提供）：粘稠的高粘性粘液和延迟的粘膜纤毛清除是囊性纤维化（CF）发病机制的重要因素，但目前可用的治疗方法对对抗粘液淤滞的疗效有限。此外，填充CF肺的生物膜有助于降低肺功能，并且通常不受当前粘液溶解剂的影响，并严重限制抗菌功效。天然降低CF痰液粘度、降低致病性生物膜的活力、凝聚力和粘度并改善粘膜纤毛清除的新型粘液溶解疗法将提供对抗呼吸下降的重要治疗进展。我们的初步数据表明，PAAG，一种可溶性的，无毒的聚阳离子多糖，对CF痰液具有强大的作用，并降低CF分离株生长的生物膜的粘度和凝聚力。预计生物膜粘附性的这种降低会增强标准抗生素的活性。基于此，我们假设PAAG可能是CF患者的有效肺粘液溶解剂，将改善气道清除率并提高抗生素活性，但需要进一步研究以了解其药理学，制剂和作用范围，以提出开发为人类治疗药物。PAAG活性的证明将提供关键的概念数据证明，并为在人类受试者中测试其活性提供科学依据。在这个项目中，我们将评估PAAG的 使用最先进的流变测定法在降低患者来源的痰液的粘度中的作用。此外，我们将证明，粘度的降低，提高粘膜纤毛清除通过评估活动的纤毛细胞单层。我们还将通过标准生物膜筛选测定和更好地再现生理条件的流动池测定来确定用于降低生物膜的凝聚力的适当剂量和处理方案。生物膜的降低的一致性也将与标准抗生素治疗相结合，以了解PAAG对CF患者治疗的增强作用。项目完成后，使用PAAG进行进一步开发将证明其作为一种新型高效CF粘液溶解治疗的概念，以解决CF患者护理中未满足的需求。

DESCRIPTION (provided by applicant): Thick hyperviscous mucus and delayed mucociliary clearance are important elements underlying cystic fibrosis (CF) pathogenesis, but currently available therapeutics exhibit limited efficacy to combat mucus stasis. In addition, biofilms that populate the CF lung contribute to reduced lung function and are typically not affected by current mucolytics and severely limit antimicrobial efficacy. Novel mucolytic therapies that innately reduce the viscosity of CF sputum, reduce the viability, cohesion and viscosity of pathogenic biofilms and improve mucociliary clearance would provide an important therapeutic advance to combat respiratory decline. Our preliminary data demonstrate that PAAG, a soluble, nontoxic polycationic polysaccharide, has robust effects on CF sputum and reduces the viscosity and cohesion of biofilms grown from CF isolates. This reduction in biofilm cohesion is anticipated to enhance activity of standard antibiotics. Based on this, we hypothesize that PAAG could be an effective pulmonary mucolytic for CF patients that will improve airway clearance and improve antibiotic activity, but requires further studies to understand its pharmacology, formulation, and breadth of effects to propose development as a human therapeutic. Demonstration of PAAG's activity will provide crucial proof of concept data and provide a scientific basis for testing its activity in human subjects. In this project, we will assess PAAG's role in reducing the viscosity of patient derived sputum using state-of-the-art rheometry. Further we will demonstrate that the reduction in viscosity improves mucociliary clearance by assessing activity on monolayers of ciliated cells. We will also determine appropriate dosing and treatment regimes for reducing the cohesion of biofilms by standard biofilms screening assays and flow cells assays that better reproduce physiologic conditions. The reduced coherence of biofilms will also be combined with standard antibiotic treatments to understand the potentiating effects of PAAG on therapies used in CF patients. Upon completion of the project, the use of PAAG for further development will have proof of concept as a new and highly effective CF mucolytic treatment to address an unmet need in CF patient care.