RT Journal Article
SR Electronic
T1 Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 812
OP 820
DO 10.1136/thoraxjnl-2020-215185
VO 77
IS 8
A1 Kim, Namho
A1 Kwak, Gijung
A1 Rodriguez, Jason
A1 Livraghi-Butrico, Alessandra
A1 Zuo, Xinyuan
A1 Simon, Valentina
A1 Han, Eric
A1 Shenoy, Siddharth Kaup
A1 Pandey, Nikhil
A1 Mazur, Marina
A1 Birket, Susan E
A1 Kim, Anthony
A1 Rowe, Steven M
A1 Boucher, Richard
A1 Hanes, Justin
A1 Suk, Jung Soo
YR 2022
UL http://thorax.bmj.com/content/77/8/812.abstract
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.