Barriers to the Pharmacologic Rescue of W1282X CFTR.

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-depend

SUBMITTER: Manfredi C 

PROVIDER: S-EPMC12781105 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature