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

• 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
• 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

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.

项目总结 囊性纤维化是一种由编码囊性纤维化的跨膜基因突变引起的遗传性疾病 电导调节器(CFTR)，粘液水合所必需的离子通道。粘液不适当的水化导致 与呼吸道炎症、慢性肺部感染和粘液纤毛功能异常有关。主要贡献者 CF的发病率和死亡率是肺功能的进行性下降。治疗方法的最新进展 针对那些具有最常见CFTR突变的人调整突变CFTR已导致显著改善 肺功能。尽管这些CFTR调节器提供了相当大的改进，但没有证据表明 随着时间的推移，肺功能继续下降，它们可以改善潜在的呼吸道炎症。这个 确定针对这种炎症的治疗方法将是确保 完全实现了CFTR调制器。来自申请人的初步体外证据表明，氯沙坦， 一种常见的降压药，具有已知的抗炎特性，可以提高高血压的疗效 CFTR调节剂在炎症中的存在。这项建议旨在加深我们对影响的了解 炎症对CFTR调节剂治疗反应的影响，并使用新的登记策略，评估是否 氯沙坦能够进一步改善那些在调制器上有CF的患者的CFTR功能 电工/电工/电工(ETI)。在目标1中，我们将在ETI上对CF患者的鼻液进行采样，并使用 回归分析，检验炎性标志物转化生长因子-1表达水平与变化的相关性 开始ETI后肺功能的变化。在目标2a中，我们将进行氯沙坦的随机双盲临床试验。 改善ETI上有CF的患者的CFTR功能，如汗液氯化物测定。我们将利用一个预言家 强化策略，只包括那些在开始ETI后汗氯化物水平持续升高的人。 此外，在目标2b中，我们将把目标2a中的反应与体外测量的cftr电流相关联。 氯沙坦和ETI处理患者鼻腔上皮细胞(NECs)，以了解其是否可以 作为体内反应的预测。申请者的长期目标是成为一名独立的 研究人员，通过应用新的、适应性的临床试验技术，评估具有 改善慢性萎缩性胃炎患者预后的潜力。他在使用体外和活体方法方面有经验。 进一步了解炎症和高血糖对粘液纤毛清除和形态的影响 基础生物统计学和临床研究方面的培训。与此提案相关的职业发展计划 将经验丰富、多样化的指导团队与高级生物统计学、适应性临床 患者来源的NECS的试验设计和应用。这将使申请者在设计和领导方面具有独特的地位 使用有效的适应性策略进行临床试验，以测试针对CF患者的下一代疗法。