論文

査読有り 国際誌
2020年9月7日

Mechanism-Based Personalized Medicine for Cystic Fibrosis by Suppressing Pseudo Exon Inclusion.

Cell chemical biology
  • Saiko Shibata
  • ,
  • Masahiko Ajiro
  • ,
  • Masatoshi Hagiwara

記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.chembiol.2020.08.013

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that compromise its chloride channel activity. Here, we present a therapeutic strategy to ameliorate RNA splicing deficiency of CFTR with a small molecule. The 3,849 + 10 kb C>T is the most common splicing mutation in CF, creating a pseudo exon with premature stop codon. We reveal that the 3,849 + 10 kb C>T-induced CFTR pseudo exon is regulated by phosphorylation of serine/arginine-rich splicing factors, and their functional inhibition by a CDC-like kinase inhibitor restores normal splicing of CFTR. Subsequent screening of our focused chemical library identified CaNDY as a rectifier of the aberrant splicing. CaNDY treatment restored normal splicing of CFTR with the 3,849 + 10 kb C>T in CF patient cells and functional CFTR protein expression in the CF model cells. Our findings open the door for mechanism-based personalized medicine for pseudo-exon-type genetic diseases.

リンク情報
DOI
https://doi.org/10.1016/j.chembiol.2020.08.013
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32905759

エクスポート
BibTeX RIS