Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier

Jung Soo Suk; Anthony J Kim; Kanika Trehan; Craig S Schneider; Liudmila Cebotaru; Owen M Woodward; Nicholas J Boylan; Michael P Boyle; Samuel K Lai; William B Guggino; Justin Hanes

doi:10.1016/j.jconrel.2014.01.007

Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier

J Control Release. 2014 Mar 28:178:8-17. doi: 10.1016/j.jconrel.2014.01.007. Epub 2014 Jan 14.

Authors

Affiliations

¹ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Ophthalmology, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore 21205, USA.
² The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA.
³ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Molecular & Cellular Biology, The Johns Hopkins University, 3400 North Charles Street, Baltimore 21218, USA.
⁴ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore 21218, USA.
⁵ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Ophthalmology, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA.
⁶ Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore 21205, USA.
⁷ Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore 21218, USA.
⁸ Johns Hopkins Adult Cystic Fibrosis Program, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore 21205, USA.
⁹ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore 21205, USA.
¹⁰ The Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Ophthalmology, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore 21231, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore 21205, USA; Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore 21218, USA. Electronic address: hanes@jhmi.edu.

Abstract

Inhaled gene carriers must penetrate the highly viscoelastic and adhesive mucus barrier in the airway in order to overcome rapid mucociliary clearance and reach the underlying epithelium; however, even the most widely used viral gene carriers are unable to efficiently do so. We developed two polymeric gene carriers that compact plasmid DNA into small and highly stable nanoparticles with dense polyethylene glycol (PEG) surface coatings. These highly compacted, densely PEG-coated DNA nanoparticles rapidly penetrate human cystic fibrosis (CF) mucus ex vivo and mouse airway mucus ex situ. Intranasal administration of the mucus penetrating DNA nanoparticles greatly enhanced particle distribution, retention and gene transfer in the mouse lung airways compared to conventional gene carriers. Successful delivery of a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity. Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy.

Keywords: Airway gene therapy; DNA nanoparticle; Mucus barrier; Multiple particle tracking.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intranasal
Adult
Animals
CHO Cells
Cricetulus
Cystic Fibrosis / metabolism
Cystic Fibrosis / therapy
Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
DNA / administration & dosage*
DNA / chemistry
Esophagus / metabolism
Female
Gastric Mucosa / metabolism
Gene Transfer Techniques*
Genetic Therapy
Humans
Lung / metabolism*
Mice, Inbred BALB C
Mucus / metabolism*
Nanoparticles / administration & dosage*
Nanoparticles / chemistry
Polyethylene Glycols / chemistry
Polyethyleneimine / chemistry
Polylysine / chemistry
Young Adult

Substances

Cystic Fibrosis Transmembrane Conductance Regulator
Polylysine
Polyethylene Glycols
Polyethyleneimine
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding