Delivery of gene therapy agents to the pulmonary system is relatively simple due to the ease of accessing the airways, however, achieving effective gene transfer in this organ has proved challenging. This is largely due to the inherent physiological and physical barriers of airways such as surface mucus, mucociliary action, basolateral receptor location of many gene vectors, and cell-to-cell tight junctions. Recently, researchers at the Centre for Nanomedicine, John Hopkins University, used nanotechnology to achieve gene transfer efficacy in both in vitro and in vivo models of muco-obstructive lung diseases.
Kim et al. (2022) used a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) to introduce a epithelial sodium channel-silencing (ENaC) plasmid into transgenic mouse models (Scnn1b-Tg) of muco-obstructive diseases, and air-liquid cultures of human bronchial epithelial cells from an individual with cystic fibrosis. Results showed that DNA-MPP carrying ENaC-silencing plasmid provided efficient downregulation of ENaC, thus reducing airway surface dehydration, mucus stasis and reduction of mucus burden in the lungs of transgenic mice. Furthermore, DNA-MPP demonstrated greater reporter gene expression in both in vitro and in vivo models when compared with mucus-impenetrable methods. In addition, a synergistic effect on therapeutic effect and transfer efficacy was observed when DNA-MPP was adjuvant to hypertonic saline, a commonly used mucus-rehydrating agent. These results provide the basis for further research into gene therapy treatments for muco-obstructive diseases such a cystic fibrosis and COPD.
Source:
Kim N, Kwak G, Rodriguez J, et al. Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier. Thorax 2022;77:812-820.
