Targeting inflammation to improve rescue of CFTR by modulator therapy

通过调节剂治疗靶向炎症以改善 CFTR 的挽救

基本信息

批准号：
10664528
负责人：
Charles Bengtson
金额：
$ 17.71万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-18 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664528
关键词：
Affect Angiotensin II Receptor Anti-Inflammatory Agents Antihypertensive Agents Biometry Blinded Childhood Chlorides Chronic Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Cross-Sectional Studies Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Defect Delta F508 mutation Development Plans Diagnostic Double-Blind Method Enrollment Ensure Epithelial Cells Evaluation FDA approved Genes Genetic Diseases Goals Human Hydration status Hyperglycemia Ibuprofen Impairment In Vitro Individual Inflammation Inflammation Mediators Ion Channel Knowledge Lead Length Life Link Liquid substance Losartan Lung Lung infections Measurement Measures Mediator Mentored Patient-Oriented Research Career Development Award Mentors Methods Morbidity - disease rate Mucociliary Clearance Mucous body substance Mutation Nasal Epithelium Nose Observational Study Outcome Patients Persons Pharmaceutical Preparations Pilot Projects Population Positioning Attribute Property Proteins Pulmonary Cystic Fibrosis Quality of life Randomized Regression Analysis Research Research Personnel Sampling Signal Transduction Surrogate Markers TGFB1 gene Techniques Testing Therapy trial Time Training Transforming Growth Factor beta Translating United States VX-770 airway inflammation airway surface liquid bronchial epithelium career development cyclooxygenase 2 cystic fibrosis patients cytokine design disease-causing mutation experience functional restoration improved improved outcome in vivo individualized medicine inflammatory marker inhibitor insight mRNA Expression microbial colonization mortality mutant next generation novel patient screening peripheral blood pre-clinical prognostic pulmonary function pulmonary function decline response secondary outcome targeted treatment treatment response

项目摘要

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.

项目摘要囊性纤维化（CF）是由编码CF跨膜的基因突变引起的遗传疾病电导调节剂（CFTR），这是粘液水合必不可少的离子通道。粘液铅的水合不当到气道感染，慢性肺部感染和异常粘膜助力功能。主要贡献者 CF的发病率和死亡率是肺功能的逐步下降。最近的疗法进步调节最常见CFTR突变的人的CFTR调制突变体CFTR导致了巨大的改善肺功能。尽管这些CFTR调节器提供了可观的改进，但仍没有证据随着肺功能随着时间的流逝，它们会改善基础气道注入。这确定针对这种炎症的疗法对于确保长期的好处至关重要 CFTR调制器已完全实现。申请人的初步体外证据表明，Losartan，具有已知抗炎特性的常见抗高血压药物可以提高 CFTR调节剂在炎症存在下。该建议旨在进一步了解影响对CFTR调节剂治疗的反应炎症，并使用新的入学策略评估是否是否 Losartan能够进一步改善调制器上CF的人的CFTR功能 ELEXACAFTOR/TEZACAFTOR/IVACAFTOR（ETI）。在AIM 1中，我们将采样ETI上CF患者的鼻液，并使用回归分析，检查炎症标志物TGF-1在变化上的表达水平的关联在AIM 2A中，我们将进行洛萨坦的随机双盲临床试验通过汗液氯化物在ETI上通过汗液氯化物测量的CFTR功能。我们将利用预后富集策略仅包括启动ETI后具有持续汗水氯化物水平的富集策略。此外，在AIM 2B中，我们将将AIM 2A中的响应与CFTR电流的体外测量相关联用Losartan和ETI处理的患者衍生的鼻皮细胞（NEC），以了解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研究人员通过应用新颖，自适应，临床试验技术，评估具有的疗法改善CF患者的预后的潜力。他先前在使用体外和体内方法方面有经验进一步了解感染和高血糖对粘膜毛的影响和正式的影响基本生物统计学和临床研究的培训。与此提案相关的职业发展计划将经验丰富的心理团队与高级生物统计学，适应性临床的额外培训配对试验设计和使用患者衍生的NEC。这将独特地将申请人定位为设计和领导使用高效的自适应策略进行临床试验，以测试CF患者的下一代疗法。