Mood-Stabilizing Drug may Treat Inherited Liver Disease

Researchers from the Children's Hospital of Pittsburg of UPMC and the University of Pittsburg School of Medicine used a primitive worm model to show that a drug that is currently used to treat agitation in both schizophrenia and dementia, may also have the potential to help as a treatment for α-1 antitrypsin (AT) deficiency--an inherited liver disease that causes severe scarring. 

In the classic form of AT deficiency, which commonly affects 1 in 3,000 live births, lies a gene mutation that leads to the production of an abnormal protein known as ATZ that's prone to clumping.

"These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation," said David H. Perlmutter, M.D., physician-in-chief and scientific director, via a press release. "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."

For the study, researchers developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans. These are harmless microscopic worms that are typically found in soil.

Previous studies involving screening of the compounds showed that fluphenazine, a drug that's approved for human use as a mood stabilizer, could potentially reduce ATZ accumulation in the worm.

Background information from the study shows that worms who produce ATZ die sooner than normal ones-with a typical life span of fewer than 20 days. Those exposed to the drug, however, had less issues with ATZ and were able to live more than a day longer than those who were left untreated.

Follow-up experiments of those treated with fluphenazine also showed a reduced accumulation of ATZ in several mammalian-cell line models, according to researchers.

"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 conlcuded, via the release. "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, according to researchers. 

More information regarding the study can be found via the Public Library of Online Science.