LUNAR LNP delivery of CFTR mRNA restores channel function and improves mucociliary clearance in ferret cystic fibrosis airways.

Abstract

Lipid nanoparticle (LNP)-based delivery of CFTR mRNA holds promise for treating pulmonary manifestations of cystic fibrosis (CF). LUNAR-CFTR is a novel proprietary lipid nanoparticle (LNP) encapsulating codon-optimized human CFTR mRNA for CFTR replacement therapy. In this study, we examined the potential of LUNAR-CFTR for delivering mRNA and restoring CFTR function in primary human and ferret airway epithelia and mucus-laden CF ferret airways. LUNAR effectively delivered CFTR, Cre, and tdTomato mRNAs into multiple airway epithelial cell types of humans and ferrets in vitro and transgenic ferrets in vivo. The LUNAR-CFTR was able to restore ion transport in polarized CF human bronchial epithelia to levels comparable to those achieved with elexacaftor/tezacaftor/ivacaftor. Mucociliary clearance (MCC) assays in CF ferrets further showed that a single dose of LUNAR-mediated human CFTR mRNA delivery improved mean MCC values by 3-fold. The improved MCC was in line with an increase in CFTR-mediated transepithelial anion transport from the CF ferret trachea transfected with LUNAR-CFTR in vivo. These findings underscore the potential of LUNAR LNP as a robust vehicle for delivering CFTR-encoding therapeutic mRNA into airway epithelial cells and underscore the utility of CF ferrets as a reliable tool to evaluate the efficiency of gene therapy in mucus-laden airways.