For the first time, researchers have developed a genetically altered animal model for cystic fibrosis (CF) that closely matches the characteristics of the disease in humans. By studying the complex and multi-organ disease process in the pig model, researchers can now better understand how the complications of CF develop, an advancement that may lead to new avenues for research in prevention and treatment.
The study, published in the Sept. 26 edition of Science, was funded in part by the National Heart, Lung, and Blood Institute (NHLBI), along with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both of the National Institutes of Health, as well as the Cystic Fibrosis Foundation.
CF is an inherited disease of the mucus-secreting glands which is caused by mutations in the gene responsible for making the protein cystic fibrosis transmembrane conductance regulator (CFTR), important for making sweat, digestive juices, and mucus. CF affects multiple organs, including the lungs, pancreas, liver, intestines, sinuses, and sex organs. In CF, mucus becomes thick and sticky, and builds up in the lungs and in the pancreas, blocking the airways, and disrupting the digestive system, resulting in recurrent, destructive infections and trouble digesting food. Respiratory failure and liver disease are the most common causes of death in CF.
Before now, mice have been the only animal model for CF. However since mice do not exhibit typical symptoms of CF, and the lung and liver diseases found in humans, finding a better model was crucial to furthering CF research.
"This represents a significant advance in research on cystic fibrosis. Until now, no animal model has come close to mimicking the disease as seen in humans. This model offers unprecedented opportunities to understand how the respiratory disease develops during childhood which may lead to novel prevention and therapeutic strategies," said Elizabeth G. Nabel, M.D., director, NHLBI.
"This new approach allows researchers to move beyond mouse models into species that are physiologically more similar to humans and that manifest the multi-organ symptoms of the disease. It is an advance for CF research as well as for the study of other diseases where the mouse model is inadequate," said NIDDK Director Griffin P. Rodgers, M.D.
A team of researchers from the University of Iowa and the University of Missouri generated male piglets lacking the CFTR gene, or possessing the most common mutation of the gene, which was identified in 1989. Newborn piglets born without CFTR had similar presentations at birth, and shortly after birth, as seen in human infants with CF, including typical abnormalities in the lungs, intestines, pancreas, and liver.
As is typical in about 15 percent of human infants with CF, newborn piglets without CFTR developed meconium ileus, an intestinal obstruction requiring corrective surgery. All of the piglets developed pancreatic insufficiency. The pigs also exhibited signs of focal biliary cirrhosis, or lesions on the liver, and gallbladder abnormalities, both typical of CF in humans.
Lung disease in CF is caused by infection and inflammation. Which comes first remains an important question for CF researchers. At birth, researchers found no evidence of infection or inflammation in the pigs, a situation similar to newborn humans with CF.
"By tracking how the lungs of these pigs respond to challenges to their respiratory systems introduced by the environment, we hope to better understand how the complications of CF progress in children," said Michael J. Welsh, M.D., University of Iowa and the Howard Hughes Medical Institute, and senior author of the study.
About 12 million Americans are carriers of an abnormal CFTR gene. Many of them do not know that they are CF carriers. About 30,000 people in the United States have CF. The median life expectancy for a person with CF is 37 years. Currently, there is no cure for CF, but life expectancy has greatly improved due to better nutrition and management of respiratory infections.
Additional funding for the research was provided by the Howard Hughes Medical Institute, Food for the 21st Century.