Thursday, 25 September 2008

Cloned Pigs with Cystic Fibrosis

Model to mimic human disease Thursday, 25 September 2008 In a first, researchers at the University of Iowa and the University of Missouri (MU) have developed a pig model for Cystic Fibrosis (CF) that appears to closely mimic the disease in human infants. The striking similarities between disease manifestations in the CF piglets and human newborns with CF suggest that this new model will help improve understanding of the disease and may also speed discovery of new treatments. The study is published in the Sept. 26 issue of Science. CF is a common hereditary disease that affects multiple organ systems, including the intestines, pancreas, and lung. Mice with CF-causing mutations have helped researchers learn more about this disease, however, differences in physiology and biology mean that mice with CF mutations do not develop many of the typical symptoms that affect humans with CF. Pig born with cystic fibrosis. Credit: University of Missouri Cystic Fibrosis (CF) continues to be a lethal disease for humans despite the identification of the problematic gene two decades ago. Many humans born with CF – the most common genetic disease in Caucasians - often die because of a lung disease developed later. Scientists have been unable to develop an animal model that develops the fatal lung disease. Now, a University of Missouri researcher is producing pigs born with cystic fibrosis that mimic the exact symptoms of a newborn with CF. The researchers are hopeful that these pigs will continue to mimic the human symptoms so the fatal lung disease can be studied and ultimately treated. "Right now, if you want to do experiments to find treatments or therapies for the lung disease that is fatal for people with CF, you would have to experiment on kids that have CF," said Randy Prather, distinguished professor of reproductive biotechnology in the MU College of Agriculture, Food and Natural Resources. "When the genetic mutation is introduced into mice, they do not display the symptoms of CF. That's why these new swine models are so important. We have been able to get them through the initial stages of the disease, which they display just like humans, and now we are just waiting for them to grow and potentially develop the lung disease so we can start experimenting in ways that have never been possible." Prather collaborated with Michael Welsh from the Howard Hughes Medical Institute at the University of Iowa. To create the genetic defect in pigs, a team led by Welsh made genetic modifications in pig cells. Prather's group then generated the genetically modified pigs from the cells using a process known as nuclear transfer. The pigs – called founder animals - that were produced carried only one copy of the mutated gene. Prather bred the pigs naturally and now many piglets have been born with CF. Once a litter is born, the piglets are immediately flown to Iowa where physicians who perform the corrective surgery on human newborns with CF do the same for the pigs. Meanwhile, MU researchers perform analysis during the transit to determine which piglets have the mutations "So far, all the mutations in the pigs have exactly mimicked the problems in humans born with CF," Prather said. "The whole cellular physiology of the pig is similar to humans. That's why having this break- through model is so exciting for the potential it has to move research on cystic fibrosis forward." "Lack of a better model has hampered our ability to answer long-standing questions in CF," 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 study's lead authors. "The CF 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. CF 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 CF 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 CF-carriers, these animals did not show disease 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 CF disease. They also showed that the CF piglets develop the same disease characteristics that are commonly seen in newborn humans with CF, including a bowel obstruction known as meconium ileus, which often is the first sign of CF in humans. The pigs also have an abnormal pancreas, liver, and gall bladder, similar to CF patients. "Thus far, the clinical, physiological and age-related appearance of disease in the pigs, as well as the organs involved, mimic CF seen in people," Stoltz said. A primary cause of death and disability in patients with CF is lung disease. However, many questions remain about how infection and inflammation leads to lung damage. In the study, the lungs of the newborn CF 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 CF 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 with CF. "Researchers can now begin to study the disease progression as it is happening, something not possible in humans," Meyerholz said. Reference: Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs Christopher S. Rogers, David A. Stoltz, David K. Meyerholz, Lynda S. Ostedgaard, Tatiana Rokhlina, Peter J. Taft, Mark P. Rogan, Alejandro A. Pezzulo, Philip H. Karp, Omar A. Itani, Amanda C. Kabel, Christine L. Wohlford-Lenane, Greg J. Davis, Robert A. Hanfland, Tony L. Smith, Melissa Samuel, David Wax, Clifton N. Murphy, August Rieke, Kristin Whitworth, Aliye Uc, Timothy D. Starner, Kim A. Brogden, Joel Shilyansky, Paul B. McCray, Jr., Joseph Zabner, Randall S. Prather, Michael J. Welsh Science 26 September 2008, Vol. 321. no. 5897, pp. 1837 – 1841, DOI: 10.1126/science.1163600 New Pig Model Could Improve Understanding of Cystic Fibrosis HHMI NEWS - September 26, 2008 ......... ZenMaster


For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

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