Journal article
Widespread airway distribution and short-term phenotypic correction of cystic fibrosis pigs following aerosol delivery of piggyBac/adenovirus
Nucleic acids research, Vol.46(18), pp.9591-9600
10/12/2018
DOI: 10.1093/nar/gky773
PMCID: PMC6182177
PMID: 30165523
Abstract
Cystic fibrosis (CF) is a common genetic disease caused by mutations in the gene coding for
cystic fibrosis transmembrane conductance regulator
(
CFTR
). Although CF affects multiple organ systems, chronic bacterial infections and inflammation in the lung are the leading causes of morbidity and mortality in people with CF. Complementation with a functional
CFTR
gene repairs this defect, regardless of the disease-causing mutation. In this study, we used a gene delivery system termed
piggyBac
/adenovirus (Ad), which combines the delivery efficiency of an adenoviral-based vector with the persistent expression of a DNA transposon-based vector. We aerosolized
piggyBac
/Ad to the airways of pigs and observed widespread pulmonary distribution of vector. We quantified the regional distribution in the airways and observed transduction of large and small airway epithelial cells of non-CF pigs, with ∼30–50% of surface epithelial cells positive for GFP. We transduced multiple cell types including ciliated, non-ciliated, basal, and submucosal gland cells. In addition, we phenotypically corrected CF pigs following delivery of
piggyBac
/Ad expressing
CFTR
as measured by anion channel activity, airway surface liquid pH, and bacterial killing ability. Combining an integrating DNA transposon with adenoviral vector delivery is an efficient method for achieving functional CFTR correction from a single vector administration.
Details
- Title: Subtitle
- Widespread airway distribution and short-term phenotypic correction of cystic fibrosis pigs following aerosol delivery of piggyBac/adenovirus
- Creators
- Ashley L Cooney - Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USABrajesh K Singh - Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USALaura Marquez Loza - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USAIan M Thornell - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USACamilla E Hippee - Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USALinda S Powers - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USALynda S Ostedgaard - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USADavid K Meyerholz - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USAChris Wohlford-Lenane - Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USADavid A Stoltz - Pappajohn Biomedical Institute and the Center for Gene Therapy for Cystic Fibrosis, The University of Iowa, Iowa City, IA 52242, USAPaul B McCray Jr - Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USAPatrick L Sinn - Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Nucleic acids research, Vol.46(18), pp.9591-9600
- Publisher
- Oxford University Press
- DOI
- 10.1093/nar/gky773
- PMID
- 30165523
- PMCID
- PMC6182177
- ISSN
- 0305-1048
- eISSN
- 1362-4962
- Grant note
- P30 DK-054759 / ; SINN15XX0 / ; ; NIH P01 HL-51670; NIH P01 HL-091842; NIH R01 HL-133089; NIH R01 HL-105821 / ; ;
- Language
- English
- Date published
- 10/12/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Internal Medicine
- Record Identifier
- 9984083283202771
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