A drug typically used to treat agitation in people with schizophrenia and dementia shows potential for treating an inherited liver disease that causes severe scarring.
In the classic form of a-1 antitrypsin (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.
“These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation,” says David H. Perlmutter, distinguished professor of pediatrics at the University of Pittsburgh School of Medicine. “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, Perlmutter’s team worked with Stephen Pak, assistant professor of pediatrics, and Gary Silverman, 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 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.
Findings are published in the journal PLOS ONE.
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.
Liver scarring is reversed
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, Silverman says.
“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 says. “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. “This is the first extensive investigation of a drug that was discovered through the C. elegans screening method,” Perlmutter says.
“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.”
The US Public Health Service and the Hartwell Foundation funded the research.
Source: University of Pittsburgh