Researchers at the University of Iowa and the University of Missouri have developed a better animal model of cystic fibrosis. Newborn pigs that have been bred with a genetic mutation for the disease are the first animals to exhibit clinical symptoms similar to those in humans with the condition. The results point to a more effective way of studying cystic fibrosis and finding drugs to treat it.
Cystic fibrosis is one of the most common life-shortening hereditary diseases. It affects 30,000 people in the United States and 70,000 worldwide. For years, scientists have tried to track the disease in mice engineered with the genetic mutation for cystic fibrosis, but the mice have not developed the trademark symptoms, including chronic lung disease. The pigs, whose organs are a closer match with humans, developed lung disease several months after birth. The researchers have published the results in the current issue of Science Translational Medicine.
Part of the motivation for the research is that, while the genetic root cystic fibrosis has long been known, it’s still unclear how this leads to lung disease.
The team found that newborn pigs with the disease had elevated levels of bacteria in their lungs. This finding may help resolve a long-standing debate –whether people with the disease are born with a hypersensitive inflammatory response that leads to lung disease, or whether inflammation occurs only when bacteria are present.
“One question looming in the field is this chicken or egg concept of whether infection comes first, or whether inflammation precedes,” says David Stoltz, assistant professor of pulmonary, critical care and occupational medicine at the University of Iowa, who was involved in the project. “It’s important to answer that question because if you now know the sequence of events of lung disease in cystic fibrosis, that could dictate how you treat it.”
Currently, physicians may choose to aggressively treat both infection and inflammation to slow the progression of lung disease. However, if researchers identify which of the two comes first in the disease, doctors could focus therapies to treat it much earlier, potentially extending lung function.
In order to identify the early effects of cystic fibrosis, Stoltz and his colleagues observed the genetically engineered pigs from birth. Within months, the pigs developed signs of lung disease, including airway inflammation, mucous accumulation, and bacterial infection.
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.