Abstract
Genome editing technologies hold great potential for correcting cystic fibrosis transmembrane conductance regulator (CFTR) mutations. However, functional delivery of such tools to cells in the lungs of cystic fibrosis (CF) patients, with overproduction of thick and sticky mucus, remains a formidable challenge and a main obstacle for the clinical translation of such therapies.
Recently, Siegwart et al. introduced the so-called SORT (selective organ targeting) principle and demonstrated that incorporation of cationic lipids endows lipid nanoparticles containing mRNA (mRNA-LNPs) with an increased ability to transfect cells in lungs upon their intravenous administration in mice1. Based on that work, we here defined a variety of mRNA-LNPs with anticipated ability to transfect cells in lungs. Formulations with desirable physicochemical properties (diameter below 150 nm, monodisperse, stable, and high mRNA encapsulation efficiency) were tested for this ability in human lung epithelium grown in air-liquid-interface (ALI) cultures and mice. Two of the tested new mRNA-LNP formulations effectively transfected cells in these models.
To the best of our knowledge, this is only the second report demonstrating transfection of fully differentiated human lung epithelium in ALI cultures2. Furthermore, we also demonstrated that after intratracheal instead of intravenous administration in mice, a significantly higher proportion of epithelial cells playing a role in CF pathology were transfected.