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Researchers at the University of Colorado Health Sciences Center, Denver, Colorado, the University of Massachusetts, Amherst, Mass., and Advanced Cell Technologies, Worcester, Mass., have successfully treated Parkinsonism in rats by using fetal brain cells from cloned cows. This research is the first demonstration that transgenic cloned animal tissue can be used in the treatment of a disease. Results of the research study will appear in the May 1 issue of the journal Nature Medicine.
Parkinson's disease, which affects an estimated one million Americans, is associated with reduced levels of dopamine in the brain. Previous research, pioneered at the CU-Health Sciences Center, has shown that symptoms of Parkinson's disease and the response to drug treatment can be improved by transplantation of human fetal dopamine cells. Other preliminary studies have suggested that animal fetal dopamine cells can survive in humans and may significantly alleviate symptoms as well.
"The use of cloned tissue is an improvement over the use of existing animal transplantation technologies because it provides us with large quantities of identical cells," said Curt R. Freed, M.D., professor, head of clinical pharmacology and toxicology, director of the CU School of Medicine's Neuroscience Program and co-author of the study. "While this early-stage research shows promising results, it will be some time before we begin human studies."
In the study published in Nature Medicine, researchers created the transgenic cells by inserting a gene marker into actively dividing fetal bovine fibroblast cells. Jose B. Cibelli, Ph.D., researcher at the University of Massachusetts and Advanced Cell Technology, and lead co-author on the study then transferred genetically altered nuclei from these cultured cells into egg cells from which the nucleus had been removed. These eggs developed into embryos, which were then transferred into cows for 45 days of further development.
"Our ability to clone and genetically modify these cells has a broad range of potential applications," said Steven Stice, Ph.D., chief scientific officer of Advanced Cell Technology, adjunct professor at the University of Massachusetts and co-author of the study. "For example, if we can engineer tissue containing specific antigens and immune modulators, we may reduce the risk of rejection and create the optimum environment for cell survival, potentially improving patient outcomes in a number of major diseases."
After demonstrating that the resulting cloned tissue yielded dopamine-producing neurons, as well as the transgene B-galactosidase, Michael Zawada, Ph.D., assistant professor of medicine at the CU-Health Sciences Center and lead co-author on the study, then transplanted these neurons into a rat model of Parkinson's disease. Behavioral tests performed eight weeks later revealed that the group which had received a transplant of the dopamine-producing neurons exhibited significant improvement in motor behavior. Successful grafting of transplanted dopamine neurons was later confirmed by cell counts in the Parkinsonian rats. The number of surviving neurons was correlated with behavioral improvement.
Parkinson's disease is a progressive disorder of the central nervous system which limits mobility. Symptoms include postural instability, gait difficulty, tremors, rigidity, and general slowing of movement. While treatment with drugs such as L-dopa has provided substantial relief for most patients with Parkinson's disease, the drugs have significant side effects and tend to lose their effectiveness after five to 20 years of use.
The first human fetal cell transplant for the treatment of Parkinson's disease in the United States was performed at the University of Colorado Hospital in November, 1988 by Dr. Freed and Robert Breeze, M.D., associate professor of neurosurgery at the CU-Health Sciences Center. Dr. Freed and his associates also were the recipients of the first National Institutes of Health grant for fetal neural transplant in January, 1994.
The combination of cloning and transgenics, or genetic engineering was demonstrated in January by researchers at Advanced Cell Technology and the University of Massachusetts through the birth of the first cloned, transgenic calves. The initial application of this technology is the development of a herd of cows with the ability to produce large quantities of therapeutic human proteins in their milk. The cloned transgenic calves carried a specific "marker" gene similar to that used in the Parkinson's study.
The researchers on the Nature Medicine paper, titled, "Somatic Cell Cloned Transgenic Bovine Neurons for Transplantation in Parkinsonian Rats," were W. Michael Zawada, Paul K. Choi, Edward D. Clarkson, Samir E. Witta, K. Pat Bell and Curt R. Freed, from the CU School of Medicine's Division of Clinical Pharmacology & Toxicology and the Neurosciences Center; Jose B. Cibelli, Paul J. Golueke, Jeff Kane, and Steven L. Stice from Advanced Cell Technology; and F. Abel Ponce de Leon, D. Joseph Jerry and James M. Robl from the University of Massachusetts.
The University of Colorado Health Sciences Center is one of four campuses in the University of Colorado system. Located in Denver, Colo., the campus includes schools of medicine, nursing, pharmacy, and dentistry, a graduate school and two hospitals.
The University of Massachusetts is the largest state university in New England and one of the leading centers of public education in the Northeast. A land-grant institution, UMass was established in 1863, and has grown to five campuses.
The 1,200-acre flagship campus in Amherst offers a rich cultural environment in the rural Pioneer Valley of western Massachusetts. During the 1997-98 school year, enrollment was 24,000: approximately 18,000 undergraduates and 6,000 graduate students.
UMass programs that have received high national rankings include the polymer science and engineering department; the linguistics department; the computer science department; the College of Engineering; and programs in communications disorders, sport studies, and creative writing.
The University's nine schools and colleges offer associate and bachelor degree programs in 94 departments, master's degrees in 70 programs and doctoral degrees in 50 programs.
Advanced Cell Technology, Inc. is a company engaged in the research and development of technologies enabling the genetic manipulation of cells to produce cloned transgenic animals for applications in pharmaceutical protein production and cell and organ transplant therapy. Formed in 1994, the company's initial focus is on the development of cloned transgenic cows to produce human serum albumin and as donors of neural cells and insulin-producing cells for the treatment of neurodegenerative diseases and diabetes, respectively. The company is also developing cloned transgenic swine for potential application in xenotransplantation.
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