Rescuing CFTR function caused by mutation specific polymorphisms in cystic fibrosis patients

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations result in cystic fibrosis (CF) disease and a broad spectrum of clinical phenotypes are observed in CF patients. One mutation, Arg117His affects the conductivity of the CFTR channel and can result in a mild or severe phenotype, influenced by co‐location of the mutation and an intron 9 polymorphism: a poly T tract varying from 5 to 9 nucleotid. The shorter ‘5T’ allele weakens the intron 9 acceptor site and promotes exclusion of exon 10 from the mature CFTR transcript, resulting in a non‐functional CFTR channel, and a more severe disease phenotyp. Manipulation of CFTR pre‐RNA splicing using antisense oligonucleotides (AOs) is a potential therapy for those CF patients with this particular mutation. This study explores antisense therapy to correct abnormal splicing of CFTR RNA and improve CFTR function. AOs targeting CFTR intron 9, around the specific 5T polymorphism, were designed and transfected into monolayer primary airway epithelial cells from a CF patient harbouring this disease‐associated polymorphism. AOs that decrease the levels of CFTR transcript missing exon 10 will then be assessed for CFTR function using an Ussing Chamber and CF patient primary epithelial cells grown at the Air‐liquid interface. We propose that corrected splicing of the CFTR 5T allele will improve function in CF patients carrying selected mutations, either alone or in combination with current therapeutics