Journal article
A Novel AAV-mediated Gene Delivery System Corrects CFTR Function in Pigs
American journal of respiratory cell and molecular biology, Vol.61(6), pp.747-754
12/2019
DOI: 10.1165/rcmb.2019-0006OC
PMCID: PMC6890402
PMID: 31184507
Abstract
Cystic fibrosis is an autosomal-recessive disease that is caused by a mutant
(cystic fibrosis transmembrane conductance regulator) gene and is characterized by chronic bacterial lung infections and inflammation. Complementation with functional
normalizes anion transport across the airway surface. Adeno-associated virus (AAV) is a useful vector for gene therapy because of its low immunogenicity and ability to persist for months to years. However, because its episomal expression may decrease after cell division, readministration of the AAV vector may be required. To overcome this, we designed an integrating AAV-based CFTR-expressing vector, termed
(PB)/AAV, carrying CFTR flanked by the terminal repeats of the
transposon. With codelivery of the
transposase, PB/AAV can integrate into the host genome. Because of the packaging constraints of AAV, careful consideration was required to ensure that the vector would package and express its CFTR cDNA cargo. In this short-term study, PB/AAV-CFTR was aerosolized to the airways of CF pigs in the absence of the transposase. Two weeks later, transepithelial Cl
current was restored in freshly excised tracheal and bronchial tissue. Additionally, we observed an increase in tracheal airway surface liquid pH and bacterial killing in comparison with untreated CF pigs. Airway surface liquid from primary airway cells cultured from treated CF pigs exhibited increased pH correlating with decreased viscosity. Together, these results show that complementing
in CF pigs with PB/AAV rescues the anion transport defect in a large-animal CF model. Delivery of this integrating viral vector system to airway progenitor cells could lead to persistent, life-long expression
.
Details
- Title: Subtitle
- A Novel AAV-mediated Gene Delivery System Corrects CFTR Function in Pigs
- Creators
- Ashley L Cooney - University of IowaIan M Thornell - University of IowaBrajesh K Singh - University of IowaViral S Shah - University of IowaDavid A Stoltz - University of IowaPaul B McCray Jr - University of IowaJoseph Zabner - University of IowaPatrick L Sinn - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.61(6), pp.747-754
- DOI
- 10.1165/rcmb.2019-0006OC
- PMID
- 31184507
- PMCID
- PMC6890402
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Grant note
- P30 DK054759 / NIDDK NIH HHS R01 HL133089 / NHLBI NIH HHS
- Language
- English
- Date published
- 12/2019
- 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; Internal Medicine
- Record Identifier
- 9984297436202771
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