Exon-skipping antisense oligonucleotides for cystic fibrosis therapy

Abstract

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 the CFTR- W1282X mutation located on CFTR exon 23. Nonsense-mediated messenger RNA (mRNA) decay (NMD) degrades the CFTR- 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 the CFTR- 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.