Antisense oligonucleotide targeting the E3 ligase RFFL potentiates CFTR modulator efficacy in CF primary bronchial epithelial cells.

ABSTRACT: Cystic fibrosis (CF) is most commonly caused by the ΔF508 mutation in the CFTR gene, leading to misfolding and degradation of the CFTR protein. Although CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) provide clinical benefit, their efficacy is limited, particularly in patients with rare or poorly responsive CFTR mutations. RFFL, an E3 ubiquitin ligase, plays a central role in peripheral quality control of CFTR, reducing its plasma membrane (PM) expression and attenuating the effects of modulators. Here, we developed antisense oligonucleotides (ASOs) containing artificial nucleic acids to selectively suppress RFFL expression. An optimized RFFL-targeting ASO enhanced the efficacy of CFTR modulators by increasing the functional PM expression of ΔF508-CFTR in primary hum

SUBMITTER: Hinata D 

PROVIDER: S-EPMC12657287 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature