Nonsense Mediated RNA Decay Pathway Inhibition Restores Expression and Function of W1282X CFTR

Rationale:The recessive genetic disease cystic fibrosis is caused by loss of function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 10% of cystic fibrosis patients have at least one allele with a nonsense mutation in CFTR. Nonsense mutations generate premature termination codons that can subject mRNA transcripts to rapid degradation through the nonsense mediated mRNA decay (NMD) pathway. Currently, there are no approved therapies specifically targeting nonsense mutations in CFTR. Objectives: Here, we identify antisense oligonucleotides (ASOs) targeting the nonsense mediated decay factor SMG1 to inhibit the NMD pathway and determine their effects on the W1282X CFTR mutation. Methods: First, we develop and validate two in vitro models of the W1282X CFTR mutation. Next, we treat these cells with antisense oligonucleotides to inhibit nonsense mediated decay and measure the effects of these treatments on W1282X expression and function. Measurements and Main Res...