MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3' untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3' UTR 298-305:miR-145-5p or 166-173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.

中文翻译：

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精确靶向miRNA位点可恢复CF支气管上皮细胞中的CFTR活性。

在囊性纤维化（CF）支气管上皮细胞（BEC）中过表达的MicroRNA负调节CFTR，并使CFTR调节剂的有益作用无效。我们假设有可能使用CFTR特异性靶位阻滞剂（TSB）逆转microRNA介导的CFTR抑制作用，并开发出针对CF的药物-设备组合吸入疗法。在一系列人CF和非CF样品以及体外模型中对微RNA的先导表达进行了定量。评估一组CFTR 3'非翻译区（UTR）特异性锁定的核酸反义寡核苷酸TSB增加CFTR表达的能力。在CF BEC模型中测量了它们单独或与CFTR调节剂组合对CFTR活性的影响。TSB封装在聚乳酸-乙醇酸（PLGA）纳米颗粒中被评估为向CF BEC传递原理的证明。靶向CFTR 3'UTR 298-305：miR-145-5p或166-173：miR-223-3p位的TSB在CF BEC中增加了CFTR表达和阴离子通道活性，并增强了依伐卡托/ lumacaftor或依伐卡托/ tezacaftor的作用。生物相容性PLGA-TSB纳米颗粒在初级BEC中促进CFTR表达，并在雾化后保留了理想的生物物理特性。封装在PLGA纳米粒子中的雾化靶向CFTR的TSB单独或与CFTR调节剂组合，可能代表一种有前途的药物-设备联合疗法，用于治疗肺CFTR功能障碍。miR-223-3p位点增加CF BEC中CFTR的表达和阴离子通道活性，并增强ivacaftor / lumacaftor或ivacaftor / tezacaftor的作用。生物相容性PLGA-TSB纳米颗粒在初级BEC中促进CFTR表达，并在雾化后保留了理想的生物物理特性。封装在PLGA纳米粒子中的雾化靶向CFTR的TSB单独或与CFTR调节剂组合，可能代表一种有前途的药物-设备联合疗法，用于治疗肺CFTR功能障碍。miR-223-3p位点增加CF BEC中CFTR的表达和阴离子通道活性，并增强ivacaftor / lumacaftor或ivacaftor / tezacaftor的作用。生物相容性PLGA-TSB纳米颗粒在初级BEC中促进CFTR表达，并在雾化后保留了理想的生物物理特性。封装在PLGA纳米粒子中的雾化靶向CFTR的TSB单独或与CFTR调节剂组合，可能代表一种有前途的药物-设备联合疗法，用于治疗肺CFTR功能障碍。