Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.
Highlights
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease
VX-445 has been introduced as a CFTR corrector when examined over chronic exposure periods (≥ 24 h)[15], we observed a detectable acute action of VX-445 in stimulating transepithelial current (It) akin to the action of a CFTR potentiator (Fig. S1)
In primary-derived non-CF human nasal epithelial (HNE) cells, acute application of VX-445 resulted in a ~ 3 μA cm−2 increase in It, which was approximately one-seventh of the total CFTR-mediated It detected (~ 20 μA c m−2) (Fig. 1A–C)
Summary
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. The development of small-molecule modulators that directly interact with CFTR to increase channel expression and/or function have proven to be highly effective in the therapeutic treatment of CF4. CFTR “correctors” stabilize misfolded protein and increase membrane expression, and CFTR “potentiators” restore channel activity. These compounds are employed in a highly precise, mutation-specific m anner[6]. Compared to Symdeko in treating C F15, there is great interest in more fully understanding the mechanism(s) of action of VX-445 in restoring function to mutant CFTR
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