Journal article
CFTR gene transfer with AAV improves early cystic fibrosis pig phenotypes
JCI insight, Vol.1(14), pp.e88728-e88728
09/08/2016
DOI: 10.1172/jci.insight.88728
PMCID: PMC5033908
PMID: 27699238
Abstract
The physiological components that contribute to cystic fibrosis (CF) lung disease are steadily being elucidated. Gene therapy could potentially correct these defects.
-null pigs provide a relevant model to test gene therapy vectors. Using an in vivo selection strategy that amplifies successful capsids by replicating their genomes with helper adenovirus coinfection, we selected an adeno-associated virus (AAV) with tropism for pig airway epithelia. The evolved capsid, termed AAV2H22, is based on AAV2 with 5 point mutations that result in a 240-fold increased infection efficiency. In contrast to AAV2, AAV2H22 binds specifically to pig airway epithelia and is less reliant on heparan sulfate for transduction. We administer AAV2H22-CFTR expressing the CF transmembrane conductance regulator (
) cDNA to the airways of CF pigs. The transduced airways expressed CFTR on ciliated and nonciliated cells, induced anion transport, and improved the airway surface liquid pH and bacterial killing. Most gene therapy studies to date focus solely on Cl
transport as the primary metric of phenotypic correction. Here, we describe a gene therapy experiment where we not only correct defective anion transport, but also restore bacterial killing in
-null pig airways.
Details
- Title: Subtitle
- CFTR gene transfer with AAV improves early cystic fibrosis pig phenotypes
- Creators
- Benjamin Steines - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USADavid D Dickey - Molecular and Cellular Biology Program, andJamie Bergen - Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USAKatherine Jda Excoffon - Department of Biological Sciences, Wright State University, Dayton, Ohio, USAJohn R Weinstein - Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USAXiaopeng Li - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USAZiying Yan - Anatomy and Cell BiologyMahmoud H Abou Alaiwa - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USAViral S Shah - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USADrake C Bouzek - Department of Internal MedicineLinda S Powers - Department of Internal MedicineNicholas D Gansemer - Department of Internal MedicineLynda S Ostedgaard - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USAJohn F Engelhardt - Anatomy and Cell BiologyDavid A Stoltz - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USAMichael J Welsh - Molecular Physiology and BiophysicsPatrick L Sinn - Howard Hughes Medical Institute, andDavid V Schaffer - Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USAJoseph Zabner - Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.1(14), pp.e88728-e88728
- Publisher
- United States
- DOI
- 10.1172/jci.insight.88728
- PMID
- 27699238
- PMCID
- PMC5033908
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- P30 ES005605 / NIEHS NIH HHS P01 HL091842 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 09/08/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Occupational and Environmental Health; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Radiation Oncology; Neurosurgery; Internal Medicine
- Record Identifier
- 9984025460502771
Metrics
26 Record Views