Production of CFTR-null and CFTR-ΔF508 heterozygous pigs by adeno-associated virus–mediated gene targeting and somatic cell nuclear transfer

Christopher S Rogers; Yanhong Hao; Tatiana Rokhlina; Melissa Samuel; David A Stoltz; Yuhong Li; Elena Petroff; Daniel W Vermeer; Amanda C Kabel; Ziying Yan; Lee Spate; David Wax; Clifton N Murphy; August Rieke; Kristin Whitworth; Michael L Linville; Scott W Korte; John F Engelhardt; Michael J Welsh; Randall S Prather

doi:10.1172/JCI34773

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Production of CFTR-null and CFTR-ΔF508 heterozygous pigs by adeno-associated virus–mediated gene targeting and somatic cell nuclear transfer

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Production of CFTR-null and CFTR-ΔF508 heterozygous pigs by adeno-associated virus–mediated gene targeting and somatic cell nuclear transfer

Christopher S Rogers, Yanhong Hao, Tatiana Rokhlina, Melissa Samuel, David A Stoltz, Yuhong Li, Elena Petroff, Daniel W Vermeer, Amanda C Kabel, Ziying Yan, …

The Journal of clinical investigation, Vol.118(4), pp.1571-1577

04/01/2008

DOI: 10.1172/JCI34773

PMCID: PMC2265103

PMID: 18324337

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Abstract

Progress toward understanding the pathogenesis of cystic fibrosis (CF) and developing effective therapies has been hampered by lack of a relevant animal model. CF mice fail to develop the lung and pancreatic disease that cause most of the morbidity and mortality in patients with CF. Pigs may be better animals than mice in which to model human genetic diseases because their anatomy, biochemistry, physiology, size, and genetics are more similar to those of humans. However, to date, gene-targeted mammalian models of human genetic disease have not been reported for any species other than mice. Here we describe the first steps toward the generation of a pig model of CF. We used recombinant adeno-associated virus (rAAV) vectors to deliver genetic constructs targeting the CF transmembrane conductance receptor ( CFTR ) gene to pig fetal fibroblasts. We generated cells with the CFTR gene either disrupted or containing the most common CF-associated mutation (Δ F508 ). These cells were used as nuclear donors for somatic cell nuclear transfer to porcine oocytes. We thereby generated heterozygote male piglets with each mutation. These pigs should be of value in producing new models of CF. In addition, because gene-modified mice often fail to replicate human diseases, this approach could be used to generate models of other human genetic diseases in species other than mice.

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Title: Subtitle: Production of CFTR-null and CFTR-ΔF508 heterozygous pigs by adeno-associated virus–mediated gene targeting and somatic cell nuclear transfer
Creators: Christopher S Rogers - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Yanhong Hao - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Tatiana Rokhlina - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Melissa Samuel - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
David A Stoltz - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Yuhong Li - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Elena Petroff - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Daniel W Vermeer - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Amanda C Kabel - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Ziying Yan - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Lee Spate - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
David Wax - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Clifton N Murphy - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
August Rieke - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Kristin Whitworth - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Michael L Linville - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Scott W Korte - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
John F Engelhardt - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Michael J Welsh - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Randall S Prather - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.118(4), pp.1571-1577
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI34773
PMID: 18324337
PMCID: PMC2265103
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 04/01/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; Radiation Oncology; Neurosurgery; Internal Medicine
Record Identifier: 9984020751602771

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