PT  - JOURNAL ARTICLE
AU  - Kim, Namho
AU  - Kwak, Gijung
AU  - Rodriguez, Jason
AU  - Livraghi-Butrico, Alessandra
AU  - Zuo, Xinyuan
AU  - Simon, Valentina
AU  - Han, Eric
AU  - Shenoy, Siddharth Kaup
AU  - Pandey, Nikhil
AU  - Mazur, Marina
AU  - Birket, Susan E
AU  - Kim, Anthony
AU  - Rowe, Steven M
AU  - Boucher, Richard
AU  - Hanes, Justin
AU  - Suk, Jung Soo
TI  - Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier
AID  - 10.1136/thoraxjnl-2020-215185
DP  - 2022 Aug 01
TA  - Thorax
PG  - 812--820
VI  - 77
IP  - 8
4099  - http://thorax.bmj.com/content/77/8/812.short
4100  - http://thorax.bmj.com/content/77/8/812.full
SO  - Thorax2022 Aug 01; 77
AB  - Introduction Inhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we introduce a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) capable of providing safe, widespread and robust transgene expression in in vivo and in vitro models of muco-obstructive lung diseases.Methods We investigated the ability of DNA-MPP to mediate reporter and/or therapeutic transgene expression in lung airways of a transgenic mouse model of muco-obstructive lung diseases (ie, Scnn1b-Tg) and in air–liquid interface cultures of primary human bronchial epithelial cells harvested from an individual with cystic fibrosis. A plasmid designed to silence epithelial sodium channel (ENaC) hyperactivity, which causes airway surface dehydration and mucus stasis, was intratracheally administered via DNA-MPP to evaluate therapeutic effects in vivo with or without pretreatment with hypertonic saline, a clinically used mucus-rehydrating agent.Results DNA-MPP exhibited marked greater reporter transgene expression compared with a mucus-impermeable formulation in in vivo and in vitro models of muco-obstructive lung diseases. DNA-MPP carrying ENaC-silencing plasmids provided efficient downregulation of ENaC and reduction of mucus burden in the lungs of Scnn1b-Tg mice, and synergistic impacts on both gene transfer efficacy and therapeutic effects were achieved when DNA-MPP was adjuvanted with hypertonic saline.Discussion DNA-MPP constitutes one of the rare gene delivery systems providing therapeutically meaningful gene transfer efficacy in highly relevant in vivo and in vitro models of muco-obstructive lung diseases due to its unique ability to efficiently penetrate airway mucus.All data relevant to the study are included in the article or uploaded as supplementary information.