title: Adenoviral gene transfer corrects the ion transport defect in the sinus epithelia of a porcine CF model.
abstract: Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17-28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.
authors.affiliation: Department of Otolaryngology-Head and Neck surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Potash
authors.forename: Tanner J
authors.initials: TJ
authors.lastname: Wallen
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.forename: Sarah
authors.initials: S
authors.lastname: Ernst
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Moninger
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gansemer
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Chang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D001692:Biological Transport; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D009297:Nasal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D012964:Sodium / Q000378:metabolism; D013552:Swine; D046509:Tissue Culture Techniques; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D049452:Green Fluorescent Proteins; D012964:Sodium; D000242:Cyclic AMP