Preclinical Development of an Anti-Mucus Drug

抗粘液药物的临床前开发

基本信息

批准号：
9317525
负责人：
Michael J Holtzman
金额：
$ 150.42万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317525
关键词：
Address Animal Model Asthma Attenuated Benchmarking Biological Assay Biological Markers Breathing Businesses Calcium Channel Cells Chemicals Chloride Channels Chronic Chronic Obstructive Airway Disease Clinical Clinical Trials Coughing Development Disease Dose Drug Design Drug Targeting Drug usage Epithelial Cells Experimental Models Family suidae Funding Future Human In Vitro Infection Inflammation Inflammatory Interleukin-13 Lead Legal patent Life Link Lung Lung diseases MAPK13 gene MUC5AC gene Modeling Morbidity - disease rate Mucins Mucous body substance Oral Pathway interactions Patients Performance Permeability Pharmaceutical Preparations Pharmacotherapy Phase Production Property Protocols documentation Public Health Rattus Reproducibility Resources Safety Secure Shortness of Breath Signal Pathway Specificity Standardization Stimulus Structure Testing Therapeutic TimeLine Toxic effect Tracheobronchial Treatment Efficacy United States National Institutes of Health Universities Washington airway obstruction analog asthmatic patient attenuation base clinical candidate commercialization cytokine design drug candidate effective therapy in vitro Assay in vivo in vivo Model inhibitor/antagonist mortality novel pre-clinical preclinical development respiratory safety study scale up screening small molecule small molecule therapeutics stem

项目摘要

DESCRIPTION (provided by applicant): This project is designed to deliver an anti-mucus drug for the treatment of respiratory airway disease. Airway diseases such as COPD and asthma are leading causes of morbidity and mortality in the U.S. and worldwide and serious forms of these diseases are linked to excess production of inflammatory mucus that obstructs the airway. However, there are no specific and effective therapies to attenuate airway mucus production. The cytokine IL-13 is implicated as a potent stimulus of airway mucus production in both asthma and COPD, and there are ongoing clinical trials of anti-IL-13 biologics. We reasoned that a small molecule to attenuate IL-13- stimulated (but not baseline) mucus production would address a major need for therapy of airway disease. Moreover, a drug targeted to airway epithelial cells themselves could offer significant advantages of specificity and efficacy. We discovered a novel pathway for mucus production that includes IL-13-induction of chloride channel calcium activated 1 (CLCA1) and then activation of mitogen activated protein kinase 13 (MAPK13). This CLCA1-MAPK13 signaling pathway was defined in experimental models but is also active in patients with excess mucus production due to COPD and likely asthma as well. Structure-based drug design led to the development of the first potent MAPK13 inhibitors, which safely attenuated IL-13-stimulated (but not baseline) mucus production in human airway epithelial cells and now appear effective in vitro and in vivo in a pig model of inflammatory airway mucus production. This Project therefore aims to deliver a safe and effective MAPK13 inhibitor for the treatment of excess mucus production found in COPD and related hypersecretory conditions. The UH2 Phase will accomplish two aims. Aim 1 will optimize lead MAPK13 inhibitors to attenuate IL-13- stimulated mucus production in human airway epithelial cells and will secure standardized in vitro ADMET evidence required for selection of a preclinical development candidate. Aim 2 will finalize conditions for IL-13- dependent airway mucus production in a large animal model that is suitable for testing anti-mucus drugs in vitro and in vivo. The UH3 Phase will advance three Aims. Aim 1 will formulate oral and inhaled candidate compounds and complete standardized in vivo ADMET-PK/PD studies. Aim 2 will proceed to safety and efficacy of candidate drugs in a large animal model of mucus production. Aim 3 will develop a protocol for use of candidate drug in humans, including safety, regulatory, and scale-up requirements for IND status. Each Aim has a defined timeline and benchmark. Together, we expect to arrive at a clinical candidate for a MAPK13 inhibitor as the first small-molecule therapeutic to control excess inflammatory mucus production. The projected market for our anti-mucus drug is hypersecretory conditions such as COPD and asthma. The Project will operate under a business plan that includes a patent filed by Washington University for proprietary anti-mucus compounds and eventual clinical trials in humans to achieve FDA approval of a MAPK13 inhibitor as an anti-mucus drug. (End of Abstract)

描述（由申请人提供）：该项目旨在提供一种抗毒学药物来治疗呼吸道气道疾病。在美国和世界范围内，COPD和哮喘等气道疾病是发病和死亡率的主要原因，这些疾病的严重形式与炎症性粘液的过量产生相关，阻碍了气道。但是，没有特定且有效的疗法可以减弱气道粘液产生。细胞因子IL-13被认为是哮喘和COPD中气道粘液产生的有效刺激，并且正在进行抗IL-13生物制剂的临床试验。我们认为，一个小分子可以减轻刺激的IL-13刺激（但不是基线）的粘液产生，将解决对气道疾病治疗的主要需求。此外，针对气道上皮细胞本身的药物可以提供特异性和功效的显着优势。我们发现了一种新的粘液产生途径，其中包括氯化物通道钙激活1（CLCA1）的IL-13诱导，然后激活有丝分裂原激活的蛋白激酶13（MAPK13）。该CLCA1-MAPK13信号传导途径是在实验模型中定义的，但由于COPD和可能的哮喘而导致粘液过量产生的患者也有效。基于结构的药物设计导致了第一个有效的MAPK13抑制剂的发展，该抑制剂安全地减弱了人类气道上皮细胞中粘液的IL-13刺激（但不是基线）的产生，现在在炎性气道粘液产生的猪模型中在体外和体内看起来有效。因此，该项目旨在提供安全有效的MAPK13抑制剂，以治疗在COPD和相关的超级分泌条件中发现的过量粘液产生。 UH2阶段将实现两个目标。 AIM 1将优化铅MAPK13抑制剂，以减轻人类气道上皮细胞中IL-13刺激的粘液产生，并确保选择临床前开发候选所需的标准化体外ADMET证据。 AIM 2将在大型动物模型中最终确定IL-13依赖气道粘液产生的条件，该模型适用于在体外和体内测试抗粘液药物。 UH3阶段将提高三个目标。 AIM 1将制定口服和吸入的候选化合物，并在体内ADMET-PK/PD研究中进行完整的标准化。 AIM 2将在大型的粘液产生动物模型中恢复候选药物的安全性和功效。 AIM 3将制定用于在人类中使用候选药物的协议，包括对IND状态的安全，监管和扩大要求。每个目标都有定义的时间表和基准。我们共同预计将获得MAPK13抑制剂的临床候选者，作为控制过量炎症性粘液产生的第一个小分子治疗。我们的抗毒物药物的预计市场是诸如COPD和哮喘之类的过度疾病。该项目将根据一项商业计划运作，其中包括华盛顿大学针对人类专有的抗糖化合物和最终临床试验提交的专利，以实现FDA批准MAPK13抑制剂作为抗糖药。（抽象的结尾）