General trends in the effects of VX-661 and VX-445 on the plasma membrane expression of clinical CFTR variants

Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a com-mon misfolded variant (DF508) that can be partially rescued by therapeutic correctorsthat restore its expression. Nevertheless, many other CF variants are insensitive to correctors. Using deep mutational scan-ning, we quantitatively compare the effects of two correctors on the plasma membrane expression of 129 CF variants. Though structural calculations suggest corrector binding provides similar stabilization to most var-iants, it's those with intermediate expression and mutations near corrector binding pockets that exhibit the greatest response. Deviations in sensitivity appear to depend on the degree of variant destabilization and the timing of misassembly. Combining correctors appears to rescue more variants by doubling the binding en-ergy and stabilizing distinct cotranslational folding transitions. These results provide an overview of rare CF variant expression and establish new tools for precision pharmacology.

Automated summary

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR chloride channel. While most CF variants can be partially rescued by therapeutic correctors, some are insensitive to them. By studying CF variants and the effects of correctors, researchers have discovered that the response to correctors depends on the level of expression and proximity to corrector binding pockets. Combining correctors can rescue more variants by stabilizing different folding transitions. These findings provide insights into CF variant expression and offer new approaches for precision pharmacology.