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 α mRNA (α_mutENaC). Lipid nanoparticles carrying α_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 α_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.

Engineered Mutant α-ENaC Subunit mRNA Delivered by Lipid Nanoparticles Reduces Amiloride Currents in Cystic Fibrosis–based Cell and Mice Models

Abstract

Advanced Search

Browse by Category

related content

Linkage Between Endosomal Escape of LNP-mRNA and Loading into EVs for Transport to Other Cells

Lipid Nanoparticles of Type-A CpG D35 Suppress Tumor Growth by Changing Tumor Immune-microenvironment and Activate CD8 T Cells in Mice