Front Pharmacol. 2024 Nov 18;15:1494327. doi: 10.3389/fphar.2024.1494327. eCollection 2024.
ABSTRACT
INTRODUCTION: Cystic Fibrosis (CF) is a genetic disease due to loss-of-function mutations of the CFTR channel. F508del is the most frequent mutation (70% of alleles in Italy), while other mutations have much lower frequency. Among them, G85E (0.4% frequency globally, 1.13% in Italy) emerges as a mutation characterized by a severe CFTR folding and trafficking defect.
METHODS: To investigate the pharmacological responsiveness of the G85E-CFTR variant, we performed a functional and biochemical characterization in heterologous expression systems and ex vivo models based on patient-derived human nasal epithelial cells (HNEC).
RESULTS: Our study demonstrated that treatment of primary airway cells with elexacaftor and tezacaftor causes a significant (although modest) rescue of CFTR function, that reaches 15%-25% of the activity measured in non-CF epithelia. A detrimental effect of chronic treatment with ivacaftor, further limiting G85E rescue, was also observed. A higher rescue of CFTR function, up to 25%-35% of the normal CFTR activity, with no evidence of negative effects upon chronic potentiator treatment, can be achieved by combining elexacaftor with ARN23765, a novel type 1 corrector endowed with very high potency. Importantly, dose-response relationships suggest that G85E might alter the binding of type 1 correctors, possibly affecting their affinity for the target.
DISCUSSION: In conclusion, our studies suggest that novel combinations of modulators, endowed with higher efficacy leading to increased rescue of G85E-CFTR, are needed to improve the clinical benefit in patients for this variant.
PMID:39624835 | PMC:PMC11608983 | DOI:10.3389/fphar.2024.1494327
