Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

David A. Stoltz, Tatiana Rokhlina, Sarah E. Ernst, Alejandro A. Pezzulo, Lynda S. Ostedgaard, Philip H. Karp, Melissa S. Samuel, Leah R. Reznikov, Michael V. Rector, Nicholas D. Gansemer, Drake C. Bouzek, Mahmoud M.Abou Alaiwa, Mark J. Hoegger, Paula S. Ludwig, Peter J. Taft, Tanner J. Wallen, Christine Wohlford-Lenane, James D. McMenimen, Jeng Haur Chen, Katrina L. BoganRyan J. Adam, Emma E. Hornick, George A. Nelson IV, Eric A. Hoffman, Eugene H. Chang, Joseph Zabner, Paul B. McCray, Randall S. Prather, David K. Meyerholz, Michael J. Welsh

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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.

Original languageEnglish
Pages (from-to)2685-2693
Number of pages9
JournalJournal of Clinical Investigation
Volume123
Issue number6
DOIs
StatePublished - Jun 3 2013

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