Abstract
Lung cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to a dysfunctional CFTR protein. Gene therapy offers promise for the treatment of lung CF. However, the development and clinical application of CF gene therapy have long been hampered by the absence of safe and highly efficient delivery vectors. In this work, a novel polymer-based gene replacement treatment approach was developed. A series of poly (β-amino esters) (PAEs) with various topological structures and chemical compositions were screened to create non-viral therapeutic systems for CFTR restoration in lung CF disease. A nanoparticle, formed by the selected highly branched PAE (HPAE) with a CpG-depleted CFTR plasmid, demonstrated CFTR gene expression and biocompatibility in lung epithelial cells, outperforming leading commercial gene transfection reagents such as Lipofectamine 3000 and Xfect. The newly developed gene therapy system successfully restored functional CFTR protein production in lung CF epithelial monolayers. This therapeutic approach holds great potential for use as an efficient and safe non-viral treatment for CF patients.