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.