TY - JOUR TI - Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis–based cell and mice models AU - Mukherjee, Anindit AU - MacDonald, Kelvin D. AU - Kim, Jeonghwan AU - Henderson, Michael I. AU - Eygeris, Yulia AU - Sahay, Gaurav T2 - Science Advances AB - 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 (αmutENaC). Lipid nanoparticles carrying αmutENaC 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 αmutENaC 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. A nanoparticle delivered ENaC-inhibitory mRNA for the treatment of cystic fibrosis. A nanoparticle delivered ENaC-inhibitory mRNA for the treatment of cystic fibrosis. DA - 2020/11/01/ PY - 2020 DO - 10.1126/sciadv.abc5911 DP - advances.sciencemag.org VL - 6 IS - 47 SP - eabc5911 LA - en SN - 2375-2548 UR - https://advances.sciencemag.org/content/6/47/eabc5911 Y2 - 2020/11/19/21:43:19 ER -