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JCI Insight. 2016 Sep 8;1(14). pii: e88730.

Lentiviral-mediated phenotypic correction of cystic fibrosis pigs.

Author information

1
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Microbiology, The University of Iowa, Iowa City, Iowa, USA.
2
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA.
3
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, USA.
4
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Pathology, The University of Iowa, Iowa City, Iowa, USA.
5
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA; Howard Hughes Medical Institute, The University of Iowa, Iowa City, Iowa, USA; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, USA.
6
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Pediatrics, The University of Iowa, Iowa City, Iowa, USA.
7
Pappajohn Biomedical Institute, The University of Iowa, Iowa City, Iowa, USA; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Microbiology, The University of Iowa, Iowa City, Iowa, USA; Department of Pediatrics, The University of Iowa, Iowa City, Iowa, USA.

Abstract

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in CF transmembrane conductance regulator (CFTR), resulting in defective anion transport. Regardless of the disease-causing mutation, gene therapy is a strategy to restore anion transport to airway epithelia. Indeed, viral vector-delivered CFTR can complement the anion channel defect. In this proof-of-principle study, functional in vivo CFTR channel activity was restored in the airways of CF pigs using a feline immunodeficiency virus-based (FIV-based) lentiviral vector pseudotyped with the GP64 envelope. Three newborn CF pigs received aerosolized FIV-CFTR to the nose and lung. Two weeks after viral vector delivery, epithelial tissues were analyzed for functional correction. In freshly excised tracheal and bronchus tissues and cultured ethmoid sinus cells, we observed a significant increase in transepithelial cAMP-stimulated current, evidence of functional CFTR. In addition, we observed increases in tracheal airway surface liquid pH and bacterial killing in CFTR vector-treated animals. Together, these data provide the first evidence to our knowledge that lentiviral delivery of CFTR can partially correct the anion channel defect in a large-animal CF model and validate a translational strategy to treat or prevent CF lung disease.

PMID:
27656681
PMCID:
PMC5027966
DOI:
10.1172/jci.insight.88730
[Indexed for MEDLINE]
Free PMC Article

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