2025-11-14 医薬基盤・健康・栄養研究所
図:気道上皮細胞におけるRFFL標的アンチセンス核酸(RFFL ASO)の働き。RFFL ASOがCFTR変異体の細胞内分解を抑制し、細胞膜上への機能的発現を促進することにより、CFTRモジュレーターの治療効果を増強させている。
<関連情報>
- https://www.nibn.go.jp/pr/press/20251114_2.html
- https://www.nibn.go.jp/pr/press/documents/20251114_.pdf
- https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(25)00310-5
E3リガーゼRFFLを標的とするアンチセンスオリゴヌクレオチドは、CF原発性気管支上皮細胞におけるCFTRモジュレーターの効能を増強する Antisense oligonucleotide targeting the E3 ligase RFFL potentiates CFTR modulator efficacy in CF primary bronchial epithelial cells
Daichi Hinata ∙ Yukari Kai ∙ Ryosuke Fukuda ∙ … ∙ Satoshi Obika ∙ Takao Inoue ∙ Tsukasa Okiyoneda
Molecular Therapy – Nucleic Acids Published:October 31, 2025
DOI:https://doi.org/10.1016/j.omtn.2025.102756
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 human bronchial epithelial (CF-HBE) cells derived from CF patients. Notably, the ASO also potentiated the effects of ETI on CFTR mutants associated with rare forms of CF, including those with limited responsiveness to modulators. In some cases, the ASO alone restored CFTR levels to those achieved by ETI treatment. These findings establish RFFL-targeting ASOs as first-in-class CFTR stabilizers and highlight their potential as a nucleic acid-based therapeutic strategy for CF caused by both common and rare CFTR mutations.
