title: Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs.
abstract: Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.
authors.affiliation: Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA. michael-welsh@uiowa.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rokhlina
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ernst
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Pezzulo
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Samuel
authors.forename: Leah R
authors.initials: LR
authors.lastname: Reznikov
authors.forename: Michael V
authors.initials: MV
authors.lastname: Rector
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gansemer
authors.forename: Drake C
authors.initials: DC
authors.lastname: Bouzek
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Abou Alaiwa
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hoegger
authors.forename: Paula S
authors.initials: PS
authors.lastname: Ludwig
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Taft
authors.forename: Tanner J
authors.initials: TJ
authors.lastname: Wallen
authors.forename: Christine
authors.initials: C
authors.lastname: Wohlford-Lenane
authors.forename: James D
authors.initials: JD
authors.lastname: McMenimen
authors.forename: Jeng-Haur
authors.initials: JH
authors.lastname: Chen
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Bogan
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Adam
authors.forename: Emma E
authors.initials: EE
authors.lastname: Hornick
authors.forename: George A
authors.initials: GA
authors.lastname: Nelson
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hoffman
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Chang
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: Randall S
authors.initials: RS
authors.lastname: Prather
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D045823:Ileus / Q000378:metabolism* / Q000473:pathology; D007231:Infant, Newborn; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D008470:Meconium / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011859:Radiography; D051381:Rats; D034421:Sus scrofa; D014132:Trachea / Q000378:metabolism / Q000473:pathology
chemical_list: D050556:Fatty Acid-Binding Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator