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液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在对抗粘液淤积方面疗效有限。此外，CF肺中的生物膜导致肺功能降低，通常不受当前黏液解药的影响，严重限制了抗菌效果。新型的黏液溶解疗法可以先天降低CF痰液的黏度，降低致病生物膜的活力、凝聚力和黏度，并改善黏液纤毛清除，这将为对抗呼吸衰退提供重要的治疗进展。我们的初步数据表明，PAAG是一种可溶、无毒的多阳离子多糖，对CF痰液有强大的作用，并降低CF分离物培养的生物膜的粘度和内聚性。这种生物膜内聚性的降低有望提高标准抗生素的活性。基于此，我们假设PAAG可能是CF患者有效的肺黏液解药，可以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，配方和作用范围，以提出作为人类治疗药物的发展。PAAG活性的演示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，我们将对PAAG进行评估

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.