Open AccessOpen reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis
Author(s) -
Wren E. Michaels,
C. PeñaRasgado,
Rusudan Kotaria,
Robert J. Bridges,
Michelle L. Hastings
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.2114886119
Subject(s) - frameshift mutation , exon skipping , exon , nonsense mutation , open reading frame , cystic fibrosis , mutation , antisense therapy , biology , rna splicing , oligonucleotide , genetics , translation (biology) , bioinformatics , medicine , rna , computational biology , cancer research , alternative splicing , messenger rna , gene , locked nucleic acid , peptide sequence , missense mutation
Significance Frameshift and nonsense mutations pose a major problem for disease therapeutic development. Eliminating these mutations from the messenger RNA by inducing exon skipping is a relatively unexplored treatment approach, though it has shown promise for some diseases. Here, we show that eliminating a common stop mutation associated with cystic fibrosis (CF), by inducing the skipping of the exon it is located in, results in a restoration of the open reading frame and recovers CFTR protein function in a manner expected to be therapeutic in CF patients who don’t currently have effective treatment options. These results are an important advancement for the CF community but also have implications for other diseases where terminating mutations are responsible for dysfunction.