Mucolytic for enhanced mucus and biofilm clearance in cystic fibrosis patients

粘液溶解剂可增强囊性纤维化患者的粘液和生物膜清除能力

基本信息

批准号：
8523995
负责人：
Shenda Baker
金额：
$ 14.99万
依托单位：
SYNEDGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523995
关键词：
Address Affect Air Anatomy Animals Anti-Bacterial Agents Antibiotic Therapy Antibiotics Bacteria Biological Assay Cell Culture Techniques Cells Clinical Clinical Trials Cystic Fibrosis Data Development Dose Drug Formulations Elements Evaluation Exhibits Human Ideal 1 In Situ In Vitro Individual Infection Liquid substance Lung Methodology Microbial Biofilms Mucociliary Clearance Mucolytics Mucous body substance Optical Coherence Tomography Pathogenesis Patient Care Patients Penetration Pharmacology Phenotype Physiological Polymers Polysaccharides Positioning Attribute Pulmonary Cystic Fibrosis Reaction Time Regimen Relative (related person)Resolution Respiratory physiology Role Schedule Severities Sputum Structure Target Populations Techniques Testing Therapeutic Thick Translating Viscosity airway epithelium antimicrobial base clinically relevant cohesion combat cystic fibrosis airway cystic fibrosis patients human subject improved monolayer mucoid novel novel therapeutic intervention particle product development public health relevance respiratory screening

项目摘要

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.

描述（由申请人提供）：浓稠的高粘性粘液和粘液纤毛清除延迟是囊性纤维化（CF）发病机制的重要因素，但目前可用的治疗方法对抗粘液淤滞的功效有限。此外，CF肺中的生物膜会导致肺功能下降，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。新型粘液溶解疗法能够自然降低 CF 痰液的粘度，降低致病性生物膜的活力、内聚力和粘度，并改善粘液纤毛清除能力，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 是一种可溶性、无毒的聚阳离子多糖，对 CF 痰液具有强大的作用，并降低 CF 分离物生长的生物膜的粘度和内聚力。生物膜凝聚力的降低预计会增强标准抗生素的活性。基于此，我们假设 PAAG 可能是 CF 患者的一种有效的肺部粘液溶解剂，可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、配方和作用广度，以建议开发为人类治疗剂。 PAAG 活性的演示将为概念数据提供重要的证明，并为测试其在人类受试者中的活性提供科学基础。在这个项目中，我们将评估 PAAG 使用最先进的流变测定法在降低患者痰液粘度方面发挥作用。此外，我们将通过评估单层纤毛细胞的活性来证明粘度的降低可以改善粘膜纤毛的清除率。我们还将通过更好地再现生理条件的标准生物膜筛选测定和流动细胞测定来确定适当的剂量和治疗方案，以减少生物膜的凝聚力。生物膜一致性的降低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。该项目完成后，使用 PAAG 进行进一步开发将证明其作为一种新型高效的 CF 粘液溶解疗法，可解决 CF 患者护理中未满足的需求。