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Researchers used fluorographic imaging to analyze treated and untreated liver cells from a mouse models to identify autophagosomes (green), cell parts that aid in enzymatic digestion. New laboratory studies suggest that a drug for the treatment of seizures may also eliminate the most common genetic cause for which children undergo liver transplants, α1-antitrypsin (AT) deficiency. Based on these studies, researchers believe the drug may even be able to address other diseases with similar traits.
Learn about the pilot study: Alpha-1 Antitrypsin Deficiency Study – Phase II
In most people, the liver produces normal AT, a protein carried through the bloodstream for use by cells in other organs. In the classic form of AT deficiency, which affects 1 in 3,000 births, a gene mutation causes the liver to instead produce an abnormal protein, ATZ, which builds up in liver cells. “This eventually leads to fibrosis, or scarring, of the organ and sets the stage for tumor development,” said David H. Perlmutter, MD, physician-in-chief and scientific director, Children’s Hospital, and Vira I. Heinz Professor and Chair of the Department of Pediatrics, University of Pittsburgh School of Medicine.
“The disease sometimes doesn’t show itself until adulthood, when the liver starts to fail due to cirrhosis or cancer,” Dr. Perlmutter noted.
Although carbamazepine is used to treat seizure disorders, recent work suggested it could enhance a natural cellular pathway, the digestive process called autophagy. On that basis, Dr. Perlmutter and his colleagues reasoned that the drug might be able to rid cells of toxic ATZ. When they treated ATZ cell lines with carbamazepine in the lab, they observed a marked decrease in ATZ, because the abnormal proteins degraded more quickly via autophagy.
Those cell tests led to experiments with mouse models with AT deficiency. Again the amount of ATZ decreased in mice treated with carbamazepine.
“The most amazing finding was that the drug reversed the fibrosis in the livers of mice, and after two weeks of treatment, the liver tissue resembled that of a healthy mouse,” Dr. Perlmutter said.
Because the anti-seizure drug, which is also known by the brand name Tegretol, is well understood by the medical community, researchers suggest that clinical trials can be rapidly initiated.
The implication that carbamazepine can step-up a cell’s autophagy machinery might have value in other disorders, such as Alzheimer’s disease, Huntington’s disease and Parkinsonism, all of which are thought to be caused by toxic effects of proteins clumping in the brain. Dr. Perlmutter and his colleagues are exploring these possibilities in preclinical studies.
The research team, whose findings were published in Science, included lead author Tunda Hidvegi, PhD, Department of Pediatrics, Simon C. Watkins, PhD, Department of Cell Biology and Physiology, George Michalopoulos, MD, PhD, Department of Pathology and other researchers from the University of Pittsburgh School of Medicine.
Children's Hospital's main campus is located in the Lawrenceville neighborhood. Our main hospital address is:
Children’s Hospital of Pittsburgh of UPMC
One Children’s Hospital Way
4401 Penn Ave.
Pittsburgh, PA 15224
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