Open AccessExon-skipping antisense oligonucleotides for cystic fibrosis therapy
Author(s) -
Young Jin Kim,
Nicole Sivetz,
Jessica Layne,
Dillon M. Voss,
Lucia Yang,
Qian Zhang,
Adrian R. Krainer
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114858118
Subject(s) - cystic fibrosis , cystic fibrosis transmembrane conductance regulator , ivacaftor , exon skipping , δf508 , messenger rna , exon , oligonucleotide , nonsense mutation , translation (biology) , mutation , microbiology and biotechnology , medicine , biology , gene , genetics , alternative splicing , missense mutation
Significance Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene, which can lead to respiratory failure. To date, there is no treatment for CF caused by theCFTR- W1282X mutation located onCFTR exon 23. Nonsense-mediated messenger RNA (mRNA) decay (NMD) degrades theCFTR- W1282X mRNA, leading to low levels of functional CFTR protein. We developed a cocktail of two antisense oligonucleotides (ASOs) that promotes the skipping of exon 23 of theCFTR- W1282X mRNA. The resulting mRNA is NMD resistant and preserves the reading frame. Its translation produces CFTR-Δex23 protein that improves CFTR activity in human bronchial epithelial cells. Our results set the stage for developing an ASO therapy for CF caused by the W1282X mutation.