Journal article
Transduction of Pig Small Airway Epithelial Cells and Distal Lung Progenitor Cells by AAV4
Cells (Basel, Switzerland), Vol.10(5), p.1014
05/01/2021
DOI: 10.3390/cells10051014
PMCID: PMC8145967
PMID: 33923029
Abstract
Cystic fibrosis (CF) is caused by genetic mutations of the CF transmembrane conductance regulator (CFTR), leading to disrupted transport of Cl- and bicarbonate and CF lung disease featuring bacterial colonization and chronic infection in conducting airways. CF pigs engineered by mutating CFTR develop lung disease that mimics human CF, and are well-suited for investigating CF lung disease therapeutics. Clinical data suggest small airways play a key role in the early pathogenesis of CF lung disease, but few preclinical studies have focused on small airways. Efficient targeted delivery of CFTR cDNA to small airway epithelium may correct the CFTR defect and prevent lung infections. Adeno-associated virus 4 (AAV4) is a natural AAV serotype and a safe vector with lower immunogenicity than other gene therapy vectors such as adenovirus. Our analysis of AAV natural serotypes using cultured primary pig airway epithelia showed that AAV4 has high tropism for airway epithelia and higher transduction efficiency for small airways compared with large airways. AAV4 mediated the delivery of CFTR, and corrected Cl- transport in cultured primary small airway epithelia from CF pigs. Moreover, AAV4 was superior to all other natural AAV serotypes in transducing ITG alpha 6 beta 4(+) pig distal lung progenitor cells. In addition, AAV4 encoding eGFP can infect pig distal lung epithelia in vivo. This study demonstrates AAV4 tropism in small airway progenitor cells, which it efficiently transduces. AAV4 offers a novel tool for mechanistical study of the role of small airway in CF lung pathogenesis in a preclinical large animal model.
Details
- Title: Subtitle
- Transduction of Pig Small Airway Epithelial Cells and Distal Lung Progenitor Cells by AAV4
- Creators
- Oliver G. Chen - Michigan State UniversitySteven E. Mather - University of IowaChristian M. Brommel - University of IowaBradley A. Hamilton - University of IowaAnnie Ehler - University of IowaRaul Villacreses - University of IowaReda E. Girgis - Spectrum HealthMahmoud Abou Alaiwa - Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USADavid A. Stoltz - University of IowaJoseph Zabner - University of IowaXiaopeng Li - Michigan State University
- Resource Type
- Journal article
- Publication Details
- Cells (Basel, Switzerland), Vol.10(5), p.1014
- DOI
- 10.3390/cells10051014
- PMID
- 33923029
- PMCID
- PMC8145967
- NLM abbreviation
- Cells
- ISSN
- 2073-4409
- eISSN
- 2073-4409
- Publisher
- Mdpi
- Number of pages
- 16
- Grant note
- LIX15XX0; LI19XX0; STOLTZ19R0; LiX16G0 / Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation Spectrum Health-MSU Alliance Corporation funds HL091842; HL51670 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 05/01/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984297598902771
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