抽象的
Trikafta, currently the leading therapeutic in cystic fibrosis (CF), has demonstrated a real clinical benefit. This treatment is the triple combination therapy of two folding correctors elexacaftor/tezacaftor (VX445/VX661) plus the gating potentiator ivacaftor (VX770). In this study, our aim was to compare the properties of F508del-CFTR in cells treated with either lumacaftor (VX809), tezacaftor, elexacaftor, elexacaftor/tezacaftor with or without ivacaftor. We studied F508del-CFTR function, maturation and membrane localisation by Ussing chamber and whole-cell patch-clamp recordings, Western blot and immunolocalisation experiments. With human primary airway epithelial cells and the cell lines CFBE and BHK expressing F508del, we found that, whereas the combination elexacaftor/tezacaftor/ivacaftor was efficient in rescuing F508del-CFTR abnormal maturation, apical membrane location and function, the presence of ivacaftor limits these effects. The basal F508del-CFTR short-circuit current was significantly increased by elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor compared to other correctors and nontreated cells, an effect dependent on ivacaftor and cAMP. These results suggest that the level of the basal F508del-CFTR current might be a marker for correction efficacy in CF cells. When cells were treated with ivacaftor combined to any correctors, the F508del-CFTR current was unresponsive to the subsequently acute addition of ivacaftor, unlike the CFTR (cystic fibrosis transmembrane conductance regulator) potentiators genistein and Cact-A1 which increased elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor-corrected F508del-CFTR currents. These findings show that ivacaftor reduces the correction efficacy of Trikafta. Thus, combining elexacaftor/tezacaftor with a different potentiator might improve the therapeutic efficacy for treating CF patients.
抽象的
由于其不稳定效果,Ivacafeafer无法提高三维县救出的F508del-cftr的功能。Ivacafacer并不排除使用不同的增强剂与三维岛相结合,因此Tripipata的有益效果低估。https://bit.ly/3dxlsjb.
脚注
Author contributions: F. Becq designed the experiments, analysed the data and contributed reagents/materials/analysis tools. F. Becq performed Ussing chamber experiments. F. Becq and T. Carrez performed and analysed patch-clamp experiments. A. Billet designed Nanion's protocols and established BHK stably expressing F508del-CFTR cells. S. Mirval carried out all cell cultures. S. Mirval and M. Lévêque performed and analysed Western blot experiments. A. Cantereau performed and analysed confocal imaging and immunolocalisation experiments. C. Coraux and E. Sage collected and provided human airway epithelial cells. F. Becq, A. Cantereau and M. Lévêque wrote and edited the manuscript.
This article has an editorial commentary:https://doi.org/10.1183/13993003.02380-2021
Conflict of interest: The authors declare that they have no conflict of interest.
Support statement: This study was supported by Vaincre La Mucoviscidose (RF20200502704). T. Carrez holds a thesis scholarship from ANRT and ManRos therapeuticsvia雪霜。A.股票是从CF Trust(SRC005)的博士后奖学金的收件人。M.Lévêque从Vaincre La MucoviCiCove持有博士后奖学金(RF20200502704)。这项工作受益于摄像机平台(Poitiers大学)的设施和专业知识。本文的资助信息已被存入Crossref Funder Registry.
- 已收到March 5, 2021.
- AcceptedJune 25, 2021.
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