Enhanced CFTR modulator efficacy in ΔF508 CFTR mouse organoids by ablation of RFFL ubiquitin ligase

• Published in: Biochemical and biophysical research communications Vol. 733; p. 150433
• Main Authors: Hinata, Daichi, Fukuda, Ryosuke, Ishiguro, Hiroshi, Kamada, Yuka, Okiyoneda, Tsukasa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2024
• Subjects: Aminophenols - pharmacology; Aminopyridines - pharmacology; Animals; Benzodioxoles - pharmacology; Benzofurans - pharmacology; CFTR; CFTR modulators; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Drug Combinations; Mice; Mice, Inbred C57BL; Mice, Knockout; Organoids; Organoids - metabolism; Pyrazoles; Pyridines; Pyrrolidines; Quinolines - pharmacology; Quinolones - pharmacology; RFFL; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Cystic fibrosis; Organoids; RFFL; CFTR modulators; CFTR
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150433

The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated. Here, we demonstrate that RFFL ablation significantly improves the effect of TEZ/ELX/IVA, resulting in enhanced function of ΔF508 CFTR in mouse organoids. Since RFFL knockout mice showed no significant abnormalities, our findings support RFFL inhibition as a promising strategy to improve CFtreatment. •RFFL knockout mice carrying ΔF508 CFTR are established.•RFFL knockout does not affect the WT CFTR channel function.•RFFL knockout enhances the efficacy of TEZ/ELX/IVA in CF mouse organoids.