title: Lentiviral-mediated phenotypic correction of cystic fibrosis pigs.
abstract: Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in CF transmembrane conductance regulator (CFTR), resulting in defective anion transport. Regardless of the disease-causing mutation, gene therapy is a strategy to restore anion transport to airway epithelia. Indeed, viral vector-deliveredCFTRcan complement the anion channel defect. In this proof-of-principle study, functional in vivo CFTR channel activity was restored in the airways of CF pigs using a feline immunodeficiency virus-based (FIV-based) lentiviral vector pseudotyped with the GP64 envelope. Three newborn CF pigs received aerosolized FIV-CFTR to the nose and lung. Two weeks after viral vector delivery, epithelial tissues were analyzed for functional correction. In freshly excised tracheal and bronchus tissues and cultured ethmoid sinus cells, we observed a significant increase in transepithelial cAMP-stimulated current, evidence of functional CFTR. In addition, we observed increases in tracheal airway surface liquid pH and bacterial killing inCFTRvector-treated animals. Together, these data provide the first evidence to our knowledge that lentiviral delivery ofCFTRcan partially correct the anion channel defect in a large-animal CF model and validate a translational strategy to treat or prevent CF lung disease.
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Departments of Microbiology.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Cooney
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Abou Alaiwa
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.|Molecular Physiology and Biophysics.
authors.forename: Viral S
authors.initials: VS
authors.lastname: Shah
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.
authors.forename: Drake C
authors.initials: DC
authors.lastname: Bouzek
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.
authors.forename: Mallory R
authors.initials: MR
authors.lastname: Stroik
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.
authors.forename: Nick D
authors.initials: ND
authors.lastname: Gansemer
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Pathology.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Internal Medicine.|Howard Hughes Medical Institute.|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.|Internal Medicine.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Pediatrics, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sinn
authors.affiliation: Pappajohn Biomedical Institute.|Roy J. and Lucille A. Carver College of Medicine.|Departments of Microbiology.|Pediatrics, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D017136:Ion Transport; D016086:Lentivirus; D013552:Swine
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator