Repurposing a Pinworm Drug to Treat Pulmonary Fibrosis

项目总结 肺纤维化是世界范围内主要的死亡原因。中位生存期仅为2.5年 它被确诊后，每年造成全球数百万人死亡，并造成数十亿美元的医疗费用。此外 死亡率、肺纤维化，其中特发性是最常见的类型，带来悲剧性的发病率。 在没有已知的特发性肺纤维化病因的情况下，很少有预防策略是实用的，直到 最近，没有可用的治疗方案。批准用于这一适应症的两种药物提供了 疾病有所缓解，但尽管如此，临床上的下降几乎总是发生的。长期目标 STXPC的目的是将一种可以逆转肺纤维化进展的药物带到临床，并提供更多 结果完全优于目前的护理标准，不良反应减少或同样可以接受。 表型筛选确定了FDA批准的一种药物，该药物在体外阻断成纤维细胞的激活并抑制 博莱霉素诱导的体内肺纤维化。在继续这些努力的同时，三个近期目标是 提议为今后的促进可持续发展研究奠定基础。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，同时也测试替代 给药途径，以及3)启动开发可吸入制剂的可行性研究 那药。为了解决作用机制，该药物激活酪蛋白激酶1的假设是 促进包括YAP/TAZ和/或β-连环蛋白在内的肌成纤维细胞表型的关键驱动因素的降解 将会受到考验。这将通过在细胞培养分析中使用遗传和药理学技术来实现。 两种形式的药物将针对肺纤维化的体内模型进行测试，包括博莱霉素和 石棉诱发的模型，通过多种给药途径建立最低有效剂量并 评估口服利用度。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可雾化溶液或悬浮剂的可行性 这种药物可以用于未来的动物试验，并可能导致临床产品。这方面的发展 配方将为肺部提供直接的局部药物，绕过以下方面的任何不足 GI吸收或肝脏代谢，并将全身副作用降至最低。肺纤维化是一种严重的 这种情况需要做出重大努力，将新的治疗方法提前用于临床测试。这项研究 研究小组已经确定了一种可重复使用的药物，该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行政手段。

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.