In a first, researchers at the University of Iowa and the University of Missouri have developed a pig model for cystic fibrosis (CF) that appears to closely mimic cystic fibrosis in human infants. This new model should improve understanding of cystic fibrosis and may also speed discovery of new cystic fibrosis treatments.

cystic fibrosis is a common hereditary disease that affects multiple organ systems, including the intestines, pancreas, and lung. Mice with cystic fibrosis causing mutations have helped researchers learn more about cystic fibrosis, however, differences in physiology and biology mean that mice with cystic fibrosis mutations do not develop many of the typical symptoms that affect humans with cystic fibrosis.

"Lack of a better model has hampered our ability to answer long-standing questions in cystic fibrosis," explained Christopher Rogers, Ph.D., a former postdoctoral fellow in internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine, and one of the cystic fibrosis study's lead authors. "The cystic fibrosis pig provides a unique opportunity to study one of the most common genetic diseases, and we hope to translate this new knowledge into better therapies and preventions."

In addition to Rogers, co-lead authors of the study were David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine, and David Meyerholz, D.V.M., Ph.D., UI assistant professor of pathology.

The senior study author was Michael Welsh, M.D., UI professor of internal medicine and molecular physiology and biophysics, who holds the Roy J. Carver Chair of Internal Medicine and Physiology and Biophysics. Welsh also is a Howard Hughes Medical Institute investigator.

Cystic fibrosis occurs when a person inherits two mutated copies of the CFTR gene leading to loss of ion channel function that adversely affects many organs. To create the cystic fibrosis pigs, the researchers used gene targeting to disrupt one copy of the normal gene in pig cells. They then cloned these altered cells to produce pigs with only one good copy of the gene. Like human cystic fibrosis-carriers, these animals did not show cystic fibrosis symptoms. The pigs were then bred naturally, and about one in four of the piglets were born with two disrupted copies of the gene.

The researchers established that piglets lacking CFTR have the abnormal ion channel activity that is a hallmark of cystic fibrosis disease. They also showed that the cystic fibrosis piglets develop the same disease characteristics that are commonly seen in newborn humans with cystic fibrosis, including a bowel obstruction known as meconium ileus, which often is the first sign of cystic fibrosis in humans. The pigs also have an abnormal pancreas, liver, and gall bladder, similar to cystic fibrosis patients.

"Thus far, the clinical, physiological and age-related appearance of cystic fibrosis disease in the pigs, as well as the organs involved, mimic cystic fibrosis seen in people," Stoltz said.

A primary cause of death and disability in patients with cystic fibrosis is lung disease. However, many questions remain about how infection and inflammation leads to lung damage. In the study, the lungs of the newborn cystic fibrosis pigs appeared similar to the lungs of their normal littermates and had no sign of infection or inflammation, possibly shedding some initial insight on the process. As the cystic fibrosis pigs mature and are exposed to airborne bacteria and viruses, the researchers hope to learn more about how and why lung disease develops in patients withcystic fibrosis.

"Researchers can now begin to study the disease progression as it is happening, something not possible in humans," Meyerholz said.

The research team included UI scientists from internal medicine, pediatrics, surgery and periodontics. In addition, Randall Prather, Ph.D., the distinguished professor of reproductive biology at MU College of Agriculture, Food and Natural Resources, and his colleagues were part of the research team.

The study was funded in part by grants from the National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health, Food for the 21st Century and the Cystic Fibrosis Foundation.