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Repurposing a Pinworm Drug to Treat Pulmonary Fibrosis

重新利用蛲虫药物治疗肺纤维化

基本信息

批准号：
10059167
负责人：
David Thomas Coleman
金额：
$ 6.33万
依托单位：
SEGUETX PANCREATIC CANCER, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059167
关键词：
Address Adverse effects Agonist American Animal Model Animal Testing Asbestos Biological Assay Biotechnology Bleomycin Caring Cause of Death Cell Culture Techniques Cells Cessation of life Chicago Clinic Clinical Clinical Trials Collaborations Contracts Data Development Diagnosis Disease Dose Down-Regulation Drug Formulations Drug Targeting Drug usage Enterobiasis Enterobius Enzymes Evaluation FDA approved Faculty Feasibility Studies Fibroblasts Fibrosis Formulation Foundations Funding Future Genetic Goals Health Health Care Costs Health Sciences Heart Human In Vitro Inhalation Intraperitoneal Injections Kidney Lead Left Legal patent Life Expectancy Liver Louisiana Lung Lung diseases Malignant Neoplasms Malignant neoplasm of pancreas Mediating Medical Modeling Morbidity - disease rate Myofibroblast Oral Oral Administration Organ Organ Size Organ failure Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Phenotype Pirfenidone Positioning Attribute Preparation Prevention strategy Principal Investigator Protein Family Proteins Pulmonary Fibrosis Research Research Support Route Signal Pathway Small Business Innovation Research Grant Sodium Chloride Solid Suspensions Symptoms Techniques Testing Therapeutic Transforming Growth Factor beta Universities Water Work absorption animal efficacy attenuation base beta catenin casein kinase I commercialization cost effective drug action drug development drug discovery drug mechanism experimental study idiopathic pulmonary fibrosis in vivo in vivo Model inorganic phosphate knock-down liver metabolism member mortality nanomolar new therapeutic target novel novel therapeutics overexpression prevent programs research clinical testing side effect small hairpin RNA transcription factor tumor progression

项目摘要

PROJECT SUMMARY Pulmonary fibrosis is a leading cause of death worldwide. With a median survival of only 2.5 years after diagnosis, it is responsible for millions of deaths worldwide and billions in health care costs each year. Besides mortality, pulmonary fibrosis, of which the idiopathic type is most common, brings about tragic morbidity. Without a known cause of idiopathic pulmonary fibrosis, very few preventive strategies are practical and until recently no therapeutic options were available. The two drugs that were approved for this indication provide some attenuation of the disease, but despite this, clinical decline almost invariably occurs. The long-term goal of STXPC is to bring a drug to the clinic that can reverse the progression of pulmonary fibrosis with more complete results than the current standards of care with reduced or equally acceptable adverse effects. Phenotypic screens identified an FDA approved drug that blocks fibroblast activation in vitro and represses bleomycin-induced pulmonary fibrosis in vivo. In continuation of these efforts, three near term objectives are proposed to set the foundation for future IND-enabling studies. These objectives are: 1) to establish the mechanism of action for the drug, 2) to validate efficacy in additional animal models while also testing alternate routes of administration, and 3) to initiate feasibility studies for the development of an inhalable formulation of the drug. To address the mechanism of action, the hypothesis that the drug activates casein kinase 1 to promote the degradation of critical drivers of the myofibroblast phenotype including YAP/TAZ and/or β-catenin will be tested. This will be accomplished using genetic and pharmacological techniques in cell culture assays. Two forms of the drug will be tested against in vivo models of pulmonary fibrosis, including bleomycin and asbestos-induced models, through multiple administration routes to establish minimum effective doses and to evaluate oral availability. The final aspect of this proposal includes a collaboration with a contract manufacturing organization to test feasibility of developing a stable nebulizable solution or suspension of the drug that could be used in future animal testing, and possibly lead to a clinical product. Development of this formulation would provide a direct topical medication for the lung, circumventing any inadequacies regarding GI absorption or liver metabolism and minimizing systemic side effects. Pulmonary fibrosis is a severe condition that warrants significant efforts to bring new therapeutics forward for clinical testing. The research team has identified a repurposable drug that holds early potential to reverse the effects of pulmonary fibrosis acting through a unique mechanism, but requires reformulation for an adequate means of administration.

项目概要肺纤维化是全世界死亡的主要原因。术后中位生存期仅为 2.5 年诊断，它每年导致全世界数百万人死亡和数十亿美元的医疗保健费用。除了死亡率，肺纤维化，其中特发性最常见，带来悲惨的发病率。由于特发性肺纤维化的病因尚不清楚，因此几乎没有什么预防策略是可行的，直到出现这种情况为止。最近没有可用的治疗选择。批准用于该适应症的两种药物提供疾病有所减轻，但尽管如此，临床衰退几乎总是发生。长期目标 STXPC 的目标是将一种可以逆转肺纤维化进展的药物推向临床，并具有更多功效。比当前护理标准更完整的结果，并且副作用减少或同样可接受。表型筛选确定了 FDA 批准的一种药物，该药物可在体外阻断成纤维细胞活化并抑制博莱霉素诱导的体内肺纤维化。继续这些努力，三个近期目标是提议为未来的 IND 支持研究奠定基础。这些目标是： 1) 建立药物的作用机制，2) 在其他动物模型中验证疗效，同时测试替代方案给药途径，以及 3) 启动开发可吸入制剂的可行性研究药物。为了解决作用机制，假设该药物激活酪蛋白激酶 1 促进肌成纤维细胞表型关键驱动因素的降解，包括 YAP/TAZ 和/或 β-连环蛋白将受到测试。这将通过细胞培养测定中的遗传和药理学技术来完成。该药物的两种形式将针对肺纤维化的体内模型进行测试，包括博莱霉素和石棉诱导模型，通过多种给药途径建立最低有效剂量并评估口服可用性。该提案的最后一个方面包括与合同的合作制造组织测试开发稳定的雾化溶液或悬浮液的可行性可用于未来动物测试的药物，并可能产生临床产品。开发此该制剂将为肺部提供直接的局部用药，避免了以下方面的任何不足：胃肠道吸收或肝脏代谢并最大限度地减少全身副作用。肺纤维化是一种严重的这种情况需要付出巨大的努力来将新的疗法用于临床测试。研究研究小组发现了一种可重新利用的药物，具有逆转肺纤维化影响的早期潜力通过独特的机制采取行动，但需要重新制定适当的管理手段。