Department of Physiology, McGill University, Montréal, Canada.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
J Cyst Fibros. 2021 Sep;20(5):895-898. doi: 10.1016/j.jcf.2021.03.011. Epub 2021 Mar 26.
Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.
Trikafta，即 elexacaftor（VX-445）、tezacaftor（VX-661）和 ivacaftor（VX-770）的组合，被批准用于治疗至少有一个 CFTR 突变 F508del 等位基因的囊性纤维化（CF）患者。虽然 VX-445 的校正功能已得到充分证实，但我们在此研究了 VX-445 单独和与 VX-770 联合使用的潜在增强剂活性。在人支气管和鼻上皮细胞中，急性添加 VX-445 分别将 VX-770 增强的 F508del-和 G551D-CFTR 电流增加了约 24%和>70%。对 G551D 和 G1244E-CFTR 通道激活与增强剂对的组合进行的分析和聚类分析表明，VX-445 的作用机制至少与先前鉴定的增强剂类别（包括 VX-770）不同，是一种附加作用。由于 VX-770 仅部分正常化 G551D-CFTR 通道功能，并且成年 G551D 患者仍会经历肺功能的进行性丧失，因此 VX-445+VX-770 联合治疗可能会为携带 G551D 和其他双重增强剂反应性突变的 CF 患者带来临床益处。
