Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Cystic fibrosis (CF) arises from mutations in the CF transmembrane regulator (CFTR) protein, impacting anion transport.
• While VX-770 (ivacaftor) benefits CF patients with G551D mutations, most CF patients have the ΔF508 mutation, requiring different treatment strategies.
• Current corrector-potentiator combination therapies show limited efficacy for the ΔF508 mutation.

Purpose of the Study:

• To investigate the impact of VX-770 on the efficacy of CFTR correctors, particularly VX-809 and VX-661, for the ΔF508 mutation.
• To elucidate the mechanisms by which VX-770 affects ΔF508-CFTR processing, stability, and function in respiratory epithelia.
• To assess the potential for optimizing potentiator therapy in combination with correctors for CF treatment.

Main Methods:

• Long-term treatment of immortalized and primary human respiratory epithelia with VX-770, alone or in combination with VX-809.
• Assessment of CFTR folding efficiency, metabolic stability, cell surface density, and channel function.
• Analysis of the influence of second-site suppressor mutations and NBD1-NBD2 interface stabilization on ΔF508-CFTR.

Main Results:

• VX-770 reduced the corrective efficacy of VX-809 and VX-661 for ΔF508-CFTR.
• VX-770 impaired ΔF508-CFTR folding and stability in endoplasmic reticulum and post-ER compartments.
• This led to decreased cell surface ΔF508-CFTR and reduced function, an effect modulated by suppressor mutations and NBD1-NBD2 interactions.

Conclusions:

• VX-770 can negatively impact the folding and stability of ΔF508-CFTR, reducing the effectiveness of corrector drugs.
• The findings highlight the need for improved potentiator design to enhance the clinical benefits of combination therapies for CF patients with the ΔF508 mutation.