title: CFTRgene transfer with AAV improves early cystic fibrosis pig phenotypes.
abstract: The physiological components that contribute to cystic fibrosis (CF) lung disease are steadily being elucidated. Gene therapy could potentially correct these defects.CFTR-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 (CFTR) 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 inCFTR-null pig airways.
authors.affiliation: Department of Internal Medicine.|Molecular and Cellular Biology Program, and.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Steines
authors.affiliation: Department of Internal Medicine.|Molecular and Cellular Biology Program, and.
authors.forename: David D
authors.initials: DD
authors.lastname: Dickey
authors.affiliation: Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Bergen
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, Ohio, USA.
authors.forename: Katherine Jda
authors.initials: KJ
authors.lastname: Excoffon
authors.affiliation: Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Weinstein
authors.affiliation: Department of Internal Medicine.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Anatomy and Cell Biology.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Abou Alaiwa
authors.affiliation: Department of Internal Medicine.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Viral S
authors.initials: VS
authors.lastname: Shah
authors.affiliation: Department of Internal Medicine.
authors.forename: Drake C
authors.initials: DC
authors.lastname: Bouzek
authors.affiliation: Department of Internal Medicine.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.affiliation: Department of Internal Medicine.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gansemer
authors.affiliation: Department of Internal Medicine.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.affiliation: Anatomy and Cell Biology.
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
authors.affiliation: Department of Internal Medicine.|Molecular and Cellular Biology Program, and.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: Department of Internal Medicine.|Molecular and Cellular Biology Program, and.|Molecular Physiology and Biophysics.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.|Howard Hughes Medical Institute, and.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sinn
authors.affiliation: Departments of Chemical and Biomolecular Engineering, Bioengineering, The Helen Wills Neuroscience Institute, Molecular and Cellular Biology, University of California, Berkeley, California, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
authors.affiliation: Department of Internal Medicine.|Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000627:therapeutic use*; D000229:Dependovirus; D005822:Genetic Vectors; D010641:Phenotype; D013552:Swine
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator