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Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier
  1. Namho Kim1,2,
  2. Gijung Kwak1,3,
  3. Jason Rodriguez1,3,
  4. Alessandra Livraghi-Butrico4,
  5. Xinyuan Zuo2,
  6. Valentina Simon1,
  7. Eric Han5,
  8. Siddharth Kaup Shenoy1,3,
  9. Nikhil Pandey6,
  10. Marina Mazur7,
  11. Susan E Birket7,8,
  12. Anthony Kim6,
  13. Steven M Rowe7,8,
  14. Richard Boucher4,
  15. Justin Hanes1,2,3,9,
  16. Jung Soo Suk1,2,3
  1. 1Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, Maryland, USA
  2. 2Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Whiting School of Engineering, Baltimore, Maryland, USA
  3. 3Department of Ophthalmology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  4. 4Marisco Lung Institute and Cystic Fibrosis Research Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  5. 5Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA
  6. 6Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
  7. 7Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama School of Medicine, Birmingham, Alabama, USA
  8. 8Department of Medicine, The University of Alabama, Birmingham, Alabama, USA
  9. 9Department of Biomedical Engineering, Environmental and Health Sciences, Oncology, Neurosurgery, and Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA
  1. Correspondence to Professor Jung Soo Suk, Center for Nanomedicine, Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, USA; jsuk{at}


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.

  • cystic fibrosis

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors NK, GK, AL-B, JH and JSS conceived and designed the study. NK, GK, AL-B, SEB, SMR and JSS prepared the draft of the manuscript. NK, GK, JR, XZ, VS, EH, SKS, NP, MM, SEB, AK, SMR, RB and JSS contributed to the acquired data and its analysis. JSS supervised this study. All authors contributed to the interpretation of the results and approved the submitted manuscript.

  • Funding The funding was provided by the National Institute of Health (NIH) (R01HL127413, R01HL136617, P30DK072482 and P30EY001765) and the Cystic Fibrosis Foundation (SUK18I0 and ROWE19R0). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

  • Competing interests The mucus-penetrating particle technology described in this publication has been developed at the Johns Hopkins University and is currently licensed to Kala Pharmaceuticals. JH is a founder of Kala Pharmaceuticals and currently serves as a consultant. JH and Johns Hopkins University own company stock; JH’s relationship with Kala Pharmaceuticals is subject to certain restrictions under university policy. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

  • Provenance and peer review Not commissioned; externally peer reviewed.