# Barriers to the Pharmacologic Rescue of W1282X CFTR

## TL;DR

This study explores how drugs can help rescue a specific genetic mutation in cystic fibrosis patients, showing that some existing treatments can improve protein function and localization.

## Contribution

The paper demonstrates that established CFTR modulators can rescue W1282X CFTR function and surface expression, revealing distinct mechanisms compared to classical F508del mutations.

## Key findings

- VX-770 increases plasma membrane levels of W1282X CFTR.
- Approved correctors like VX-809 and VX-661 enhance W1282X CFTR channel activity.
- G418 increases W1282X mRNA and protein without suppressing the stop codon.

## Abstract

W1282X CFTR is the most prevalent CF-causing variant
among cystic
fibrosis patients of Ashkenazi descent and a mutational defect for
which targeted drug therapy is not available. We show that administration
of the potentiator VX-770 can augment levels of truncated W1282X CFTR
in the plasma membrane, demonstrating that an established gating activator
(i.e., “potentiator”) also rescues W1282X protein expression
and surface localization (i.e., “corrector” function).
Additionally, acute in vitro treatments with approved modulators VX-809
or VX-661 result in immediate potentiation of W1282X-dependent ion
transport, showing that F508del CFTR correctors also augment W1282X
CFTR channel activity. To investigate the mechanism, we tested a CFTR
variant (G551D) exhibiting higher levels of CFTR-dependent potentiation
following corrector treatment. Clinically approved CFTR correctors
VX-445, VX-121, and VX-809 elicited potentiation of G551D CFTR. Forskolin
dose dependence and molecular dynamic simulations indicated that corrector
molecules promote acute CFTR gating by modifying protein conformation
and enhancing heterodimerization of nucleotide binding domains, leading
to potentiator-like effects. Although W1282X is poorly responsive
to “readthrough” agents such as G418, the drug unexpectedly
increases W1282X mRNA, augments surface-localized (truncated) protein,
and promotes CFTR function, even in the absence of detectable stop
codon suppression. Moreover, unlike other CFTR mutations such as F508del,
proteasome blockade using ALLN partially rescues W1282X at the plasma
membrane. These results highlight ways in which detailed mechanistic
analysis and modulator profiling are needed to characterize CFTR mutations
such as W1282X and that modulator function in rare variants can be
quite distinct from classical findings based strictly upon F508del
CFTR.