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用 Lumacaftor-Ivacaftor（Orkambi）治疗囊性纤维化纯合子患者可恢复循环单个核细胞中缺陷的 CFTR 通道功能。

Treatment of Cystic Fibrosis Patients Homozygous for with Lumacaftor-Ivacaftor (Orkambi) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells.

机构信息

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.

Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.

出版信息

Int J Mol Sci. 2020 Mar 31;21(7):2398. doi: 10.3390/ijms21072398.

DOI:10.3390/ijms21072398
PMID:32244302
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7177453/
Abstract

The treatment of cystic fibrosis (CF) patients homozygous for the mutation with Orkambi, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability in the clinical response was also observed. The aim of this study was to evaluate the response to Orkambi in a small cohort of F508del/F508del patients ( = 14) in terms of clinical and laboratory parameters, including ex vivo CFTR activity in mononuclear cells (MNCs), during a 12-month treatment. Patients responded with an increase in percent predicted forced expiratory volume in 1 s (FEV%) and body mass index (BMI) as well as with a decrease in white blood cell (WBC) total counts and serum C-reactive protein (CRP) levels, although not significantly. Sweat chloride and CFTR-dependent chloride efflux were found to decrease and increase, respectively, as compared with pre-therapy values. CFTR and BMI showed a statistically significant correlation during Orkambi treatment. Clustering analysis showed that CFTR, BMI, sweat chloride, FEV%, and WBC were strongly associated. These data support the notion that CFTR-dependent chloride efflux in MNCs should be investigated as a sensitive outcome measure of Orkambi treatment in CF patients.

摘要

用奥马卡比（一种校正剂（卢美卡法特）和 CFTR 蛋白突变体的增强剂（依伐卡托））治疗囊性纤维化（CF）纯合子 突变患者可改善部分呼吸功能。然而，也观察到临床反应存在很大差异。本研究旨在通过 12 个月的治疗，评估奥马卡比在一小群 F508del/F508del 患者（n = 14）的临床和实验室参数（包括单核细胞（MNCs）中 CFTR 活性的体外测定）方面的反应。患者的用力呼气量（FEV%）和体重指数（BMI）预测百分比增加，白细胞（WBC）总数和血清 C 反应蛋白（CRP）水平降低，但无统计学意义。与治疗前相比，发现汗液氯化物和 CFTR 依赖性氯离子外排分别降低和增加。CFTR 和 BMI 在奥马卡比治疗期间显示出统计学显著相关性。聚类分析表明，CFTR、BMI、汗液氯化物、FEV%和 WBC 密切相关。这些数据支持这样一种观点，即 MNCs 中 CFTR 依赖性氯离子外排应作为 CF 患者奥马卡比治疗的敏感疗效指标进行研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b812/7177453/ff03904e84ba/ijms-21-02398-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b812/7177453/ff03904e84ba/ijms-21-02398-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b812/7177453/30da65641607/ijms-21-02398-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b812/7177453/283a3ce19c82/ijms-21-02398-g003.jpg
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