Exon-skipping antisense oligonucleotides for cystic fibrosis therapy
Young Jin Kim, Nicole Sivetz, Jessica Layne, Dillon M. Voss, Lucia Yang, Qian Zhang, Adrian R. Krainer
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.