Engineered mutant ?-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models.

ABSTRACT: Cystic fibrosis (CF) results from mutations in the chloride-conducting CF transmembrane conductance regulator (CFTR) gene. Airway dehydration and impaired mucociliary clearance in CF is proposed to result in tonic epithelial sodium channel (ENaC) activity, which drives amiloride-sensitive electrogenic sodium absorption. Decreasing sodium absorption by inhibiting ENaC can reverse airway surface liquid dehydration. Here, we inhibit endogenous heterotrimeric ENaC channels by introducing inactivating mutant ENaC ? mRNA (?mutENaC). Lipid nanoparticles carrying ?mutENaC were transfected in CF-based airway cells in vitro and in vivo. We observed a significant decrease in macroscopic as well as amiloride-sensitive ENaC currents and an increase in airway surface liquid height in CF airway cells. Similarly, intranasal transfection of ?mutENaC mRNA decreased amiloride-sensitive nasal potential difference in CFTRKO mice. These data suggest that mRNA-based ENaC inhibition is a powerful strategy for reducing mucus dehydration and has therapeutic potential for treating CF in all patients, independent of genotype.

SUBMITTER: Mukherjee A 

PROVIDER: S-EPMC7673816 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature