Antisense oligonucleotide targeting of mRNAs encoding ENaC subunits α, β, and γ improves cystic fibrosis-like disease in mice

Background: The epithelial sodium channel ENaC consists of three subunits encoded by Scnn1a, Scnn1b, and Scnn1g and increased sodium absorption through this channel is hypothesized to lead to mucus dehydration and accumulation in cystic fibrosis (CF) patients. Methods: We identified potent and specific antisense oligonucleotides (ASOs) targeting mRNAs encoding the ENaC subunits and evaluated these ASOs in mouse models of CF-like lung disease. Results: ASOs designed to target mRNAs encoding each ENaC subunit or a control ASO were administered directly into the lungs of mice. The reductions in ENaC subunits correlated well with a reduction in amiloride sensitive channel conductance. In addition, levels of mucus markers Gob5, AGR2, Muc5ac, and Muc5b, periodic acid-Schiff s reagent (PAS) goblet cell staining, and neutrophil recruitment were reduced and lung function was improved when levels of any of the ENaC subunits were decreased. Conclusions: Delivery of ASOs targeting mRNAs encoding each of the three ENaC subunits directly into the lung improved disease phenotypes in a mouse model of CF-like lung disease. These findings suggest that targeting ENaC subunits could be an effective approach for the treatment of CF. (C) 2018 Published by Elsevier B.V.