The researchers took lung tissue cultures from both modified and normal piglets, and performed multiple tests to look for early signs of lung inflammation, including elevated white blood cell counts. They also did gene expression profiles related to inflammation. The group found no major differences between the disease and control groups before the disease group began showing symptoms, suggesting that people born with cystic fibrosis are not necessarily born with a hypersensitive immune response.
Going a step further, the team tested the newborns’ ability to fight off infection by introducing Staphylococcus aureus into their lungs, a bacteria commonly found in infants and children with cystic fibrosis. After four hours, researchers found the bacteria lingered in the lungs of the modified pigs, whereas their healthy counterparts were able to completely get rid of it.
“This study says that it seems to be the bacteria triggering the immune response,” says William Guggino, director of the Cystic Fibrosis Research Development Program at Johns Hopkins University. “To have an animal model where you could apply drugs and see if they work to correct this bacterial infection is a pretty big advance.”
Alice Prince, professor of pediatrics in pharmacology at Columbia University, who was not involved in the study, says studying cystic fibrosis in pigs makes sense physiologically. “I think it’s a very promising model,” he says. “The immunology of pigs is more like people, and the airway cells in the pig lung are more like a human than in a mouse, so you could try a lot more therapies than you can with mice.”
While the pigs reproduce clear clinical trademarks of the human disease, the researchers found that, like humans with cystic fibrosis, the piglets are born with a bowel obstruction that, without surgery, is 100 percent fatal. “These are incredibly expensive animals,” says Craig Gerard, chief of the division for respiratory services at Children’s Hospital in Boston.
Stoltz and his team plan to test a variety of drugs in the modified pigs, including compounds that counteract the effects of the relevant gene mutation. In cystic fibrosis, the mutated gene, CFTR, alters the activity of a key ion channel in the membranes of organs like the lungs and pancreas, causing thick mucus to build up, which exacerbates lung function. Scientists have recently identified drug compounds that improve the activity of the ion channel, which could potentially restore ion transport and lung function.