Targeting inflammation to improve rescue of CFTR by modulator therapy

项目摘要 囊性纤维化（CF）是一种遗传性疾病，由编码CF跨膜蛋白的基因突变引起。 电导调节器（CFTR），粘液水合所必需的离子通道。粘液水合不当导致 呼吸道炎症、慢性肺部感染和纤毛功能异常。该主要缴款国 CF的发病率和死亡率是肺功能的进行性下降。治疗的最新进展， 对于那些最常见的CFTR突变的人，调节突变的CFTR已经导致了显著的改善， 肺功能尽管这些CFTR调节剂提供了相当大的改善，但没有证据表明 随着时间的推移，肺功能持续下降，它们改善了潜在的气道炎症。的 确定针对这种炎症的治疗方法对于确保治疗的长期益处至关重要。 CFTR调制器完全实现。申请人的初步体外证据表明， 一种常见的抗高血压药物，具有已知的抗炎特性，可以提高 CFTR调节剂在炎症的存在下。这项建议旨在进一步了解 炎症对CFTR调节剂治疗的反应，并使用新的招募策略， 氯沙坦能够进一步改善CF患者的CFTR功能 依他卡托/替扎卡托/依伐卡托（ETI）。在目标1中，我们将对ETI上的CF患者的鼻液进行采样， 回归分析，检测炎症标志物TGF-β 1的表达水平与变化的相关性， 对肺功能的影响在aim 2a中，我们将进行一项氯沙坦的随机、双盲临床试验 改善ETI CF患者的CFTR功能（通过汗液氯化物测量）。我们将利用一个预测 通过仅包括那些在开始ETI后汗液氯化物水平持续升高的人来实施富集策略。 此外，在目标2b中，我们将目标2a中的响应与CFTR电流的体外测量相关联。 用氯沙坦和ETI处理的患者源性鼻上皮细胞（NEC），以了解其是否可以 用作体内反应的预测。申请人的长期目标是成为独立的 研究者，通过应用新的、适应性的临床试验技术，评估 改善CF患者结局的潜力。他有使用体外和体内方法的经验 为了进一步了解炎症和高血糖对粘膜纤毛清除和形式的影响， 基础生物统计学和临床研究培训。与此建议书相关的职业发展计划 将经验丰富、多元化的指导团队与高级生物统计学、适应性临床 试验设计和患者源性NEC的利用。这将使申请人能够独特地设计和领导 临床试验使用有效的适应性策略来测试CF患者的下一代疗法。

PROJECT SUMMARY Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), an ion channel essential for mucus hydration. Improper hydration of mucus leads to airway inflammation, chronic pulmonary infections and abnormal mucociliary function. The major contributor to morbidity and mortality in CF is a progressive decline in lung function. Recent advances in therapies that modulate mutant CFTR for those with the most common CFTR mutations have led to dramatic improvements in lung function. Despite the considerable improvements afforded by these CFTR modulators, there is no evidence that they improve underlying airway inflammation as lung function continues to decline over time. The identification of therapies that target this inflammation will be critical to ensuring that the long-term benefits of CFTR modulators are fully realized. Preliminary in vitro evidence from the applicant demonstrates that losartan, a common anti-hypertensive medication with known anti-inflammatory properties, can improve the efficacy of CFTR modulators in the presence of inflammation. This proposal aims to further our understanding of the impact of inflammation on response to CFTR modulator therapy and, using a novel enrollment strategy, evaluate if losartan is able to further improve CFTR function in those with CF on the modulator elexacaftor/tezacaftor/ivacaftor (ETI). In aim 1, we will sample the nasal fluid of those with CF on ETI and, using regression analysis, examine the association of expression levels of the inflammatory marker TGF-1 on change in lung function after starting ETI. In aim 2a, we will conduct a randomized, double-blind clinical trial of losartan to improve CFTR function, as measured by sweat chloride, in those with CF on ETI. We will utilize a prognostic enrichment strategy by including only those with the persistently elevated sweat chloride levels after starting ETI. Additionally, in aim 2b, we will correlate the response in aim 2a with in vitro measurement of CFTR current in patient-derived nasal epithelial cells (NECs) treated with losartan and ETI in order to understand if it could be utilized as a prediction of in vivo response. The long-term goal of the applicant is to become an independent investigator who, through application of novel, adaptive, clinical trial techniques, evaluates therapies which have the potential to improve outcomes of those with CF. He has prior experience in using in vitro and in vivo methods to further understanding of the effects of inflammation and hyperglycemia on mucociliary clearance and formal training in basic biostatistics and clinical research. The career development plan associated with this proposal pairs an experienced, diverse mentoring team with additional training in advanced biostatistics, adaptive clinical trial design and utilization of patient-derived NECs. This will uniquely position the applicant to design and lead clinical trials using efficient, adaptive strategies to test the next generation of therapies for those with CF.