Repurposing a Pinworm Drug to Treat Pulmonary Fibrosis

项目摘要 肺纤维化是世界范围内的主要死亡原因。中位生存期只有2.5年， 诊断，它是负责数以百万计的世界各地的死亡和数十亿美元的医疗保健费用，每年。除了 肺纤维化，其中特发性类型是最常见的，带来了悲惨的发病率。 由于特发性肺纤维化的病因不明，很少有预防策略是可行的，直到 最近没有可用的治疗选择。两种被批准用于该适应症的药物提供了 疾病的一些衰减，但尽管如此，临床下降几乎总是发生。远景目标 STXPC的目的是为临床带来一种药物，可以逆转肺纤维化的进展， 与目前的护理标准相比，具有更低或同样可接受的不良反应的完整结果。 表型筛选确定了一种FDA批准的药物，可在体外阻断成纤维细胞活化并抑制 博来霉素诱导的体内肺纤维化。为继续这些努力，三个近期目标是 建议为未来的IND赋能研究奠定基础。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，同时还测试替代药物 给药途径，和3）启动可行性研究，以开发一种可吸入制剂， 流毒为了说明作用机制，假设药物激活酪蛋白激酶1， 促进肌成纤维细胞表型的关键驱动因子的降解，包括雅普/TAZ和/或β-连环蛋白 会得到考验这将在细胞培养试验中使用遗传和药理学技术来完成。 将针对肺纤维化的体内模型测试两种形式的药物，包括博来霉素和 通过多种给药途径建立最低有效剂量， 评价口服利用度。该提案的最后一个方面包括与合同的合作 生产组织测试开发稳定的可雾化溶液或悬浮液的可行性。 这种药物可以用于未来的动物试验，并可能导致临床产品。发展这一 该制剂将为肺提供直接的局部药物，避免了关于 胃肠道吸收或肝脏代谢和最大限度地减少全身副作用。肺纤维化是一种严重的 这种情况需要做出重大努力，为临床试验带来新的治疗方法。研究 一个研究小组已经确定了一种可重复利用的药物，该药物具有逆转肺纤维化影响的早期潜力 通过独特的机制发挥作用，但需要重新制定适当的管理手段。

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.