Project 2: PK/PD requirements for mucolytic therapeutic agents in vitro and in vivo

项目2：粘液溶解治疗剂体内外PK/PD要求

基本信息

批准号：
10001600
负责人：
Richard Charles Boucher
金额：
$ 47.8万
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/10001600
关键词：
Acetates Adhesions Adhesives Aerosols Animals Ascaris suum Asthma Back Basic Science Biological Models Body Weight decreased Cell Culture Techniques Chronic Obstructive Airway Disease Cleaved cell Clinic Clinical Clinical Data Collaborations Data Development Disease Dose Drug Delivery Systems Environment Epithelial Cells Equilibrium Exhibits Exposure to Focal Adhesions Formulation Frequencies Gel Generations Goals Health Human Hydration status In Vitro Infection Inflammation Inhalation Interleukin-1 beta Interleukin-13 Lead Liquid substance Lung Lung diseases MUC5AC gene MUC5B gene Measures Modeling Modification Molecular Weight Mucins Mucolytics Mucous body substance Mus Oxidation-Reduction Oxidative Stress Parents Patients Pharmaceutical Preparations Phenotype Polymers Population Property Public Health Pyroglyphidae Reducing Agents Rehydrations Research Personnel Resistance Role Safety Saline Sheep Speed Sulfhydryl Compounds Surface System Testing Therapeutic Therapeutic Agents Toxicology Translating United States airway inflammation airway obstruction airway remodeling asthma model asthmatic base biophysical analysis bronchial epithelium clinical candidate crosslink data modeling design dithiol effective therapy esterase extracellular flexibility in vivo in vivo Model inflammatory lung disease model design mouse model mucus clearance mucus-associated lung diseases novel novel therapeutics pharmacokinetics and pharmacodynamics preclinical development programs relative effectiveness response tool

项目摘要

Project 2 has focused on the hypotheses that: (1) hyperconcentrated (dehydrated) mucus produces airway mucus adhesion/plaques that drive the progression of muco-obstructive lung diseases; and, (2) that clearance of these plugs/plaques will be therapeutically useful in patients with the muco-obstructive phenotype. Recent data have indicated that once mucostasis has occurred, modification of mucus plaques may occur that make them “permanent” and resistant to rehydration therapies. Our biophysical analyses suggest that mucin molecular weight (MW) reduction will be effective in clearing mucus in this setting without rehydration. Further, Project 2 hypothesizes that by the generation of disease specific models, that effectively mimic the extracellular mucins/mucus targets of our disease populations, will produce useful information to guide the clinical projects with respect to selection of drug doses, dosing frequency, requirement for an active vehicle (e.g., hypertonic saline) and generate data on “off target” redox effects. In collaboration with tPPG investigators, we have established that in CF (and COPD) MUC5B is the dominant mucin obstructing airways. In contrast, we have identified that MUC5AC is the dominant airway mucin in subjects with asthma. Accordingly, we have generated appropriate cell culture, small animal, and sheep models that mimic the mucin dominance phenotype for each disease entity. Utilizing these tools, Project 2 will measure and compare the pharmacodynamics and pharmacokinetic properties of two different, but complementary, thiol reducing agent clinical candidates. P2176 is a di-thiol compound with rapid reductive activity (Kcat) whereas the mono-thiol P2114 has a slower intrinsic reductive (Kcat) activity. Both molecules share features designed to retain the molecules on the airway surface and both molecules have their thiols “capped” by acetate groups that are cleaved by esterases on airway surfaces to liberate active compounds. The relative effectiveness/properties of each molecule will be tested in: (1) in vitro HBE cultures designed to mimic the extracellular MUC5AC/MUC5B ratios of CF/COPD (Il-1β treated) and asthma (IL-13 treated); (2) mouse models of CF/COPD (βENaC) mice, and asthma (house dust mite treated) to measure clearance of mucus plugs after aerosol drug delivery; and, large animal sheep models, including wild-type, Ascaris suum exposed, and HNE/CF172 treated sheep to measure pharmacodynamics and pharmacokinetic parameters. Based on these data, and GLP toxicology studies, a lead molecule doses/dosing frequency, and a vehicle will be selected. Importantly, Project 2 will also utilize information gained from Project 1/Project 2 studies and clinical Projects 3 and 4 to study backup compounds as improvements in the frontrunner become identified/implemented in the parent thiol compound chassis. Thus the overarching goal of the 2b Project is to identify the optimal drug properties, balancing rate of mucin thiol reduction, duration of activity, and safety, to develop a new class of muco-clearance assisting agents that focus on mucin MW reduction that can be delivered alone or in combination with hydrating agents.

项目2的重点是：（1）高浓度（脱水）粘液产生气道粘液粘附/斑块，可驱动粘液刺激性肺部疾病的进展；（2）清理这些塞子/斑块中有热蛋白表型的患者对热有用。最近的数据表明，一旦发生粘液症，可能会发生粘液斑块的修饰它们“永久性”并抵抗补液疗法。我们的生物物理分析表明粘蛋白分子量（MW）的减小将有效地在这种情况下清除粘液而无需再合化。此外，项目2假设通过疾病特定模型的产生，有效地模仿我们疾病种群的细胞外粘蛋白/粘液靶标将产生有用的信息来指导临床项目有关药物剂量的选择，给活性车辆的剂量频率，需求（例如，高渗盐水）并生成有关“关闭目标”氧化还原效应的数据。与TPPG合作研究人员已经确定，在CF（和COPD）中，MUC5B是阻塞气道的主要粘蛋白。相反，我们已经确定MUC5AC是哮喘受试者中的主要气道粘蛋白。彼此之间，我们产生了适当的细胞培养，小动物和模仿粘蛋白的绵羊模型每个疾病实体的优势表型。利用这些工具，项目2将测量和比较两种不同但完整的硫醇还原剂的药效动力学和药代动力学特性临床候选人。 P2176是具有快速降低活性（KCAT）的二硫醇化合物，而单硫醇 P2114具有较慢的固有降低（KCAT）活性。这两个分子共享旨在保留的特征气道表面和两个分子上的分子的硫醇由乙酸根组“盖住” 在气道表面上的酯酶裂解以释放活性化合物。相对有效性/特性每个分子将在：（1）旨在模仿细胞外MUC5AC/MUC5B的体外HBE培养物中 CF/COPD（已处理IL-1β）和哮喘（治疗IL-13）的比率；（2）CF/COPD（βenac）小鼠的小鼠模型，和哮喘（经过室内尘螨），以测量气溶胶药物输送后粘液塞的清除；和，大型动物绵羊模型，包括野生型，Ascaris suum暴露，HNE/CF172处理过的绵羊测量药效和药代动力学参数。基于这些数据和GLP毒理学将选择研究，铅分子剂量/给药频率和车辆。重要的是，项目2也将利用从项目1/项目2研究和临床项目3和4中获得的信息来研究备份在父母硫醇化合物中识别/实现的Frontrunner的改进化合物化合物机壳。 2B项目的总体目标是确定最佳药物特性，平衡速率减少粘蛋白硫醇，活动持续时间和安全性，以开发一类新的粘液清除率侧重于粘蛋白MW降低的剂，可以单独递送或与保湿剂结合使用。