Barriers to the Pharmacologic Rescue of W1282X CFTR

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• The W1282X variant is a prevalent cause of cystic fibrosis (CF) in Ashkenazi Jewish individuals.
• Targeted drug therapies for W1282X CFTR are currently unavailable.
• Understanding W1282X CFTR mutation mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the efficacy of existing CFTR modulators on the W1282X variant.
• To elucidate the underlying mechanisms by which modulators affect W1282X CFTR.
• To explore novel therapeutic strategies for W1282X-associated cystic fibrosis.

Main Methods:

• In vitro treatment of W1282X CFTR expressing cells with CFTR potentiators (e.g., VX-770) and correctors (e.g., VX-809, VX-661).
• Assessment of W1282X CFTR protein expression, surface localization, and ion transport function.
• Molecular dynamic simulations and forskolin dose-response studies on G551D CFTR.
• Investigation of readthrough agents (G418) and proteasome inhibitors (ALLN) on W1282X CFTR.

Main Results:

• VX-770 (potentiator) increased W1282X CFTR in the plasma membrane, exhibiting corrector-like function.
• Approved correctors (VX-809, VX-661) potentiated W1282X CFTR-dependent ion transport.
• Readthrough agent G418 unexpectedly increased W1282X mRNA and surface protein, enhancing CFTR function.
• Proteasome blockade partially rescued W1282X CFTR at the plasma membrane.

Conclusions:

• Existing CFTR modulators demonstrate unexpected efficacy for the W1282X variant, acting as both correctors and potentiators.
• Mechanistic studies reveal that correctors can acutely enhance CFTR gating by altering protein conformation.
• Modulator function for rare CFTR variants like W1282X can differ significantly from established effects on F508del CFTR, necessitating tailored therapeutic approaches.