Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

Posted by & filed under Part 21: MEMBRANE TRANSPORT DISORDERS.

The group of Michael Welsh has recently published a paper showing that CFTR expression in the intestine is sufficient to rescue meconium ileus in cystic fibrosis (CF) pigs.

CF pigs develop disease with features remarkably similar to those of CF patients, 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, thus making difficult to evaluate the airway disease in this model. The authors of the paper generated transgenic CF pigs expressing porcine CFTR cDNA in the intestine. 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. Nevertheless, the intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype.  Finding that transgenic expression of CFTR induced anion transport in the newborn ileum and rescued the meconium ileus phenotype suggests that correcting Cl and/or HCO3 transport across intestinal epithelia is sufficient to prevent meconium ileus. Moreover, intestinal CFTR expression prevented meconium ileus despite the presence of pancreatic disease. Therefore, the known association between the occurrence of meconium ileus and pancreatic insufficiency is likely related to the presence of more severe CFTR mutations rather than to a causal role for pancreatic exocrine insufficiency in meconium ileus. Importantly, this model may be of value for understanding the pathogenesis of the airway disease and for testing new preventions and therapies that have been difficult to investigate because of the higher early mortality related to meconium ileus.

http://www.jci.org/articles/view/68867

Posted by Nicola Brunetti-Pierri, MD, FACMG

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