In the classic form of AT deficiency, which affects 1 in 3,000 live births, a gene mutation leads to production of an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to clumping, explained David H. Perlmutter, M.D., physician-in-chief and scientific director, Children's Hospital, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, Pitt School of Medicine.
"These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation," Dr. Perlmutter said. "If we could find a drug that slows or stops this process, we might be able to prevent the need for liver transplantation in these patients."
To find that drug, Dr. Perlmutter's team worked with Pitt's Stephen Pak, Ph.D., assistant professor of pediatrics, and Gary Silverman, M.D., Ph.D., Twenty-five Club Professor of Pediatrics, Cell Biology and Physiology, who developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans, a harmless microscopic worm or nematode typically found in soil. Previous experiments conducted by Drs. Pak and Silverman, in which more than 2,000 compounds were screened, showed that fluphenazine, a drug approved for human use as a mood stabilizer, could reduce ATZ accumulation in the worm, so the team studied it further.
Worms that produce ATZ die sooner than normal ones, which typically have a life span of fewer than 20 days. Those that were exposed to fluphenazine, however, had lower burdens of ATZ and lived more than a day longer that untreated animals. The lifespan of normal worms was unchanged by fluphenazine exposure. The researchers also labeled with fluorescent markers intracellular structures called autophagosomes, which help clear abnormal proteins out of the cell in a process called autophagy. Fluphenazine exposure was associated with a greater presence of autophagosomes, suggesting that increased autophagy led to reduced ATZ accumulation.
Follow-up experiments showed that fluphenazine reduced ATZ accumulation in several mammalian-cell line models of AT deficiency, D. Silverman said.
"We found when we gave this drug for three weeks to mice with the disease, autophagy is activated, the abnormal protein load is diminished, and liver scarring is reversed. It's truly amazing," he said. "And because fluphenazine is already being safely prescribed for other conditions, it should be easier to bring it to clinical trials for AT deficiency."
The project also reveals the power of the worm model to rapidly screen drug candidates, Dr. Perlmutter noted.
"This is the first extensive investigation of a drug that was discovered through the C. elegans screening method," he said. "It's remarkable that you can take a completely unbiased, high-content screen using a primitive organism and end up identifying a drug that reduces the accumulation of an abnormal protein in mammalian cell lines and a living mouse. It's proof-of-principle of this research pipeline. Furthermore, this drug is very similar pharmacologically to carbamazepine, another mood stabilizer that we found to enhance autophagy and reverse liver fibrosis in the mouse model of α1-antitrypsin deficiency."
Other co-authors of the paper include Jie Li, M.D., Ph.D., Linda P. O'Reilly, Ph.D., Joshua A. Benson, Yan Wang, Ph.D., Tunda Hidvegi, Ph.D., Pamela Hale, Christine Dippold, and Michael Ewing, all of the University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh of UPMC.
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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 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
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.
About Children's Hospital of Pittsburgh of UPMC
Regionally, nationally, and globally, Children's Hospital of Pittsburgh of UPMC is a leader in the treatment of childhood conditions and diseases, a pioneer in the development of new and improved therapies, and a top educator of the next generation of pediatricians and pediatric subspecialists. Children's Hospital has fulfilled this mission since its founding in 1890. Children's is named consistently to several elite lists of pediatric hospitals, including ranking 7th among children's hospitals and schools of medicine (FY 2012) in funding for pediatric research provided by the National Institutes of Health, and is one of 10 pediatric hospitals in the United States named to U.S. News & World Report's Honor Roll of America's "Best Children's Hospitals" for 2013-2014.
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