Development of Novel Mycolytic Therapies for Lung Disease

肺部疾病新型溶菌疗法的开发

基本信息

批准号：
10001578
负责人：
Richard Charles Boucher
金额：
$ 217.4万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001578
关键词：
Acute Age Allergens Animal Model Animals Asthma Biochemical Biological Assay Biological Markers Biophysics Body Weight decreased Chronic Chronic Obstructive Airway Disease Clinic Clinical Trials Design Complement Cross-Over Studies Cystic Fibrosis DNA Data Decision Making Development Disease Doctor of Philosophy Dose Drug Formulations Drug Kinetics Environment Exposure to Formulation Frequencies Gel Generations Goals Health Human Hydration status Image In Vitro Infection Inflammation Inhalation Knowledge Lung Lung diseases MUC5AC gene MUC5B gene Magnetic Resonance Imaging Measurement Measures Modeling Modification Molecular Weight Monoclonal Antibody F19 Mucins Mucociliary Clearance Mucolytics Mucous body substance Mus Obstruction Outcome Oxidation-Reduction Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Population Pre-Clinical Model Property Public Health Pulmonary Function Test/Forced Expiratory Volume 1 Radioisotopes Reducing Agents Research Research Design Resistance Role Safety Saline Sheep Spirometry Sputum Sulfhydryl Compounds Surface Target Populations Testing Therapeutic Therapeutic Agents Translations United States airway hyperresponsiveness airway obstruction arm asthmatic base biophysical analysis biophysical properties cystic fibrosis patients density drug development effective therapy effectiveness testing experience experimental analysis extracellular improved in vivo in vivo imaging light scattering mucus clearance mucus-associated lung diseases novel novel therapeutics oxidant stress patient population pharmacokinetics and pharmacodynamics predict clinical outcome primary endpoint safety testing stress reduction ventilation

项目摘要

The overarching therapeutic goal for the UNC tPPG renewal is to clear the hyperconcentrated, adherent mucus that promotes airways obstruction, inflammation, and infection. A straightforward approach to treat muco-obstructive diseases is to rehydrate airway surfaces. However, recent experimental and biophysical analyses have identified that thickened adherent mucus can be modified to generate “permanent” gels resistant to clearance by hydration. The therapeutic strategy identified to clear permanent mucus gels is the reduction mucin molecular weight (MW). Consequently, the tPPG is configured to take advantage of novel thiol mucin MW reducing agents, e.g., a di-thiol P2176 and a monothiol P2114, and has assembled a full drug development team to quickly and safely bring these molecules into patient populations in need. The tPPG will be overseen by a decision making Project Development/Statistical Core (Core A, Richard C. Boucher, MD, PI) that will guide selection and development of thiol class compounds and oversee selection of drug dose, dosing frequency, drug formulation and clinical trial designs. Projects/Cores overseen include: Project 1 (Michael Rubinstein, PhD., PI: Mechanism of Action of Mucolytics in Improving Mucus Clearance in Lung Disease), will focus on the relative roles of MUC5AC (an “asthma” mucin) vs. MUC5B (a “CF/COPD” mucin) as disease specific targets and generate biophysical measurements to assist in compound selection and as biophysical assays for the clinic. Project 2 (Richard C. Boucher, MD, PI: PK/PD Requirements for Mucolytic Therapeutic Agents In Vitro and In Vivo), will utilize in vitro, small animal, and large animal models to compare P2176 with P2114 with respect to mucolytic dose, dosing frequency, and the requirement for a hypertonic saline (HS) formulation. Project 3 (Scott Donaldson, MD, PI: Treatment of Mucostasis and Airways Obstruction in Cystic Fibrosis with a Novel Mucolytic), will test the safety and short term efficacy of P2176/P2114 in CF populations. Project 4 (David Peden, MD, PI: Treatment of Mucostasis and Airways Obstruction in Asthma with a Novel Mucolytic), will test on the safety and short-term efficacy of P2176/P2114 in patients with asthma under basal and allergen challenged conditions. The projects will be supported by three cores: (1) Core B, Analytics for Mucolytics (Mehmet Kesimer, PhD, PI), will provide a broad spectrum of biophysical and biochemical measurements of mucolysis; (2) Core C, In-vivo Imaging of Mucus Obstruction and Clearance (William Bennett, PhD, PI) will provide imaging of subjects, including radio-nuclide mucociliary clearance measurements and F19-MR ventilation imaging; and, (3) Core D, The Pharmacokinetics/Pharmacodynamics (Charles Esther, MD, PhD, PI) will provide measurements of pharmacodynamic and drug pharmacokinetic measurements of thiol compounds. The tPPG deliverable is to mobilize our experienced drug development group to advance a novel class of IND-ready therapeutic compounds into patients in need of pulmonary mucus clearance, including, asthma, CF, ultimately COPD.

UNC TPPG更新的总体治疗目标是清除过度浓缩的粘附器促进气道目标，感染和感染的粘液。一种直接的治疗方法粘膜刺激性疾病是补充气道表面。但是，最近的实验和生物物理分析已经确定，可以修饰粘附粘液增厚以产生“永久”凝胶通过水合抵抗清除率。确定清除永久性粘液凝胶的理论策略是还原粘蛋白分子量（MW）。因此，TPPG配置为利用新型硫醇粘蛋白MW还原剂，例如Di-Thiol P2176和单硫醇P2114，并组装了完整的药物开发团队可以快速安全地将这些分子带入需要的患者人群中。 TPPG会受到决策项目开发/统计核心的监督（Core A，Richard C. Boucher，医学博士，PI）这将指导选择和开发硫醇类化合物并监督药物剂量的选择频率，药物配方和临床试验设计。监督的项目/核心包括：项目1（迈克尔） Rubinstein，PI。专注于MUC5AC（一种“哮喘”粘蛋白）与MUC5B（一种“ CF/COPD”粘蛋白）的相对作用特定靶标并生成生物物理测量值，以协助化合物选择和作为生物物理诊所的测定法。项目2（Richard C. Boucher，医学博士，PI：PK/PD的粘液溶剂治疗要求体外和体内的代理）将利用体外，小动物和大型动物模型将P2176与 P2114关于脂肪剂量，给药频率以及高渗盐水（HS）的要求公式。项目3（Scott Donaldson，医学博士，PI：囊性粘膜和气道阻塞的处理纤维化具有新型的脂肪溶解），将测试CF种群中P2176/P2114的安全性和短期效率。项目4（医学博士David Peden，PI：通过新颖粘液溶解），将测试p2176/p2114对基本哮喘患者的安全性和短期效率和过敏原挑战条件。这些项目将得到三个核心的支持：（1）核心B，分析粘液溶剂（Mehmet Kesimer，PhD，PI）将提供广泛的生物物理和生化。粘液解的测量；（2）Core C，粘液阻塞和清除的体体成像（William） Bennett博士，PI）将提供受试者的成像，包括无线核苷酸清除率测量和F19-MR通气成像；（3）核心D，药代动力学/药效学（查尔斯·埃斯特（Charles Esther），医学博士，博士，PI）将提供药效和药物动力学的测量硫醇化合物的测量。 TPPG可交付是为了动员我们经验丰富的药物开发小组将新型的辅助治疗化合物推向需要肺部粘液的患者清除，包括哮喘，CF，最终是COPD。