Commonly Used Seizure Drug Could Treat Severe Genetic Liver Disease Finds Children’s Hospital of Pittsburgh of UPMC and Pitt Team

The liver scarring of α1-antitrypsin (AT) deficiency, the most common genetic cause for which children undergo liver transplantation, might be reversed or prevented with a medication that has long been used to treat seizures, according to findings from Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine that will published in Science and are available online today through the Science Express website.

Because the anti-seizure drug is familiar to doctors and has a well-understood safety profile, clinical trials could begin immediately to see whether it can help patients with AT deficiency, said senior author David H. Perlmutter, M.D., physician-in-chief and scientific director, Children’s Hospital, and Vira I. Heinz Professor and Chair of the Department of Pediatrics, Pitt School of Medicine.

In the classic form of the disease, which affects 1 in 3,000 live births, a gene mutation leads to an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to aggregation.

“These aggregates of ATZ accumulate in the liver cells and eventually lead to scarring, or fibrosis, of the organ and set the stage for tumor development,” Dr. Perlmutter said. “The disease sometimes doesn’t show itself until adulthood, when the liver starts to fail due to cirrhosis or cancer.”

For the study, he and his colleagues treated an ATZ cell line with carbamazepine, or Tegretol. Although this drug has been used primarily to treat seizure disorders, some recent work has suggested that it could enhance a natural cellular pathway called autophagy, or self-digestion, and so the Pitt researchers reasoned that it might be able to rid the cells of the toxic aggregated ATZ.

They found that carbamazepine did, indeed, cause a marked decrease in ATZ because the abnormal proteins were degraded more quickly via autophagy, and so they did another experiment in a mouse model of AT deficiency.

“The amount of ATZ decreased in the livers of the mice treated with carbamazepine,” Dr. Perlmutter said. “The most amazing finding was that the drug reversed the fibrosis in the livers of the mice and, after two weeks of treatment, the liver tissue resembled that of a healthy mouse.”

The ability of carbamazepine and drugs like it to “soup up” the cell’s autophagy machinery might have value in other disorders ― such as Alzheimer’s disease, Huntington’s disease and Parkinsonism ― that are thought to be caused by toxic effects of protein clumping in the brain. Dr. Perlmutter and his colleagues are now exploring these possibilities in preclinical studies.

The team included lead author Tunda Hidvegi, Ph.D., Department of Pediatrics, Simon C. Watkins, Ph.D., Department of Cell Biology and Physiology, George Michalopoulos, M.D., Ph.D., Department of Pathology, and other researchers from the Pitt School of Medicine.

The study was funded by the National Institutes of Health, Children’s Hospital and UPMC.

About Children’s Hospital

Renowned for its outstanding clinical services, research programs and medical education, Children’s Hospital of Pittsburgh of UPMC has helped establish the standards of excellence in pediatric care. From ambulatory care to transplantation and cardiac care, talented and committed pediatric experts care for infants, children and adolescents who make more than 1 million visits to Children’s, its many neighborhood locations and Children’s Community Pediatrics practices each year.

Children’s also has been named consistently to several elite lists of pediatric health care facilities, including ranking tenth in total dollars and seventh in number of awards (NIH FY 2008) in funding provided by the National Institutes of Health (NIH), and is named one of the top pediatric hospitals in the United States by U.S. News & World Report. For more information about Children’s Hospital, visit www.chp.edu.

About the University of Pittsburgh School of Medicine

As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997 and now ranks fifth in the nation, according to preliminary data for fiscal year 2008. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see www.medschool.pitt.edu.