Effect of elexacaftor and bamocaftor on the metabolic and thermal stability of the F508del-CFTR protein in human airway epithelial cells.

IF 3.5 2区 医学 Q1 PHYSIOLOGY
Thomas Carrez, Sandra Mirval, Christine Barrault, Florian Devetter, Clarisse Vandebrouck, Frédéric Becq
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引用次数: 0

Abstract

Trikafta (elexacaftor/tezacaftor/ivacaftor, ETI) is approved for cystic fibrosis (CF) patients with at least one F508del mutation in the CFTR gene or another responsive mutation based on in vitro data. However, the pharmacological effects of ETI on F508del-CFTR remain incompletely defined in vitro. To explore the mechanisms underlying Trikafta's clinical efficacy, we used primary bronchial epithelial cells from F508del homozygous patients and CFBE41o- cells expressing F508del-CFTR. We assessed CFTR maturation, turnover, chloride transport, and thermal stability under various ETI concentrations and treatment durations at physiological temperature using electrophysiology (Ussing chamber, patch-clamp) and biochemical assays. We found that ETI efficacy on F508del-CFTR is strongly influenced by both treatment duration and concentration. Reducing ETI from standard doses, i.e. E (3 μM), T (18 μM), I (1 μM), to 33%, 11%, 3.3%, and 1.1% decreased function and maturation, but 33% retained most of the corrective effect. After 2 hours of treatment, around 50% of the CFTR-dependent current was preserved, unlike in untreated cells. Notably, replacing elexacaftor with bamocaftor further improved F508del-CFTR maturation and function compared to ETI, though it did not affect the rate of current decline over time. These findings highlight the importance of optimizing ETI dose and exposure duration, as both significantly affect F508del-CFTR stability and function. The retained efficacy at reduced concentrations suggests possible individualized dosing strategies, particularly for patients experiencing adverse effects with full-dose ETI.

萃取物和萃取物对人气道上皮细胞F508del-CFTR蛋白代谢和热稳定性的影响
Trikafta (elexacaftor/tezacaftor/ivacaftor, ETI)被批准用于CFTR基因中至少有一个F508del突变或另一个应答性突变的囊性纤维化(CF)患者。然而,ETI对F508del-CFTR的体外药理作用尚未完全确定。为了探索Trikafta临床疗效的机制,我们使用了来自F508del纯合子患者的原代支气管上皮细胞和表达F508del- cftr的cfbe410细胞。我们利用电生理学(使用腔室、膜片钳)和生化分析评估了不同ETI浓度和生理温度下处理时间下CFTR的成熟度、周转率、氯离子转运和热稳定性。我们发现ETI治疗F508del-CFTR的疗效受治疗时间和浓度的强烈影响。将ETI从标准剂量E (3 μM)、T (18 μM)、I (1 μM)分别降低到33%、11%、3.3%和1.1%,使功能和成熟度下降,但33%的ETI保留了大部分矫正效果。治疗2小时后,与未治疗的细胞不同,大约50%的cftr依赖电流被保存下来。值得注意的是,与ETI相比,用bamocaftor替代elexaftor进一步提高了F508del-CFTR的成熟度和功能,尽管它不影响当前随时间下降的速度。这些发现强调了优化ETI剂量和暴露时间的重要性,因为这两者都会显著影响F508del-CFTR的稳定性和功能。降低浓度后的疗效提示可能的个体化给药策略,特别是对于使用全剂量ETI出现不良反应的患者。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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