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

Anindit Mukherjee, Kelvin D. MacDonald, Jeonghwan Kim, Michael I. Henderson, Yulia Eygeris, Gaurav Sahay

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Article numbereabc5911
    JournalScience Advances
    Volume6
    Issue number47
    DOIs
    StatePublished - Nov 18 2020

    ASJC Scopus subject areas

    • General

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