Barriers and recent advances in non-viral vectors targeting the lungs for cystic fibrosis gene therapy

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in CFTR genes that affect chloride ion channel. The CF is a good nominee for gene therapy as the asymptomatic carriers are phenotypically normal, and the desired cells are accessible for vector delivery. Gene therapy shows promising effects involving the correction of gene or replacement of the mutant gene with the functional one. Accordingly, various viral and non-viral carriers have been investigated. Although viral vectors are efficient, they have some problems, including mutagenesis, host immune response, higher toxicity, and costliness. On the other hand, non-viral vectors have less toxicity and immunogenic response and are easier to prepare. For a successful gene therapy, the cargo must be delivered to the target site. However, various barriers are faced by non-viral vectors, which make the gene delivery to the target site difficult. Extracellular barrier, which is the first barrier, include nucleases, negatively charged serum proteins, blood cells, and activated immune system. Ciliated epithelium, mucus gel, apical surface glycocalyx, and plasma membrane come in the second category of the barriers. Furthermore, the third category, which is related to the intracellular barriers, includes endosome and lysosome, cytoplasmic nucleases, viscous environment of cytoplasm with different proteins, and finally nuclear membrane. Various approaches have been proposed to increase the systematic delivery of vectors and enhance their efficiency. Some of these approaches include surface coating with inert polymers, modification of surface charge with anionic polymers, and enhancement of endocytosis and reduction of toxicity by using polyethylene glycol. This review paper was conduct to highlight the barriers faced by non-viral vectors when carrying a genetic payload to the lungs. This study also involved the investigation of the strategies and different types of modifications targeted toward the improvement of the efficiency of non-viral vectors.