Clinical trials could start in the next six months testing a drug already used extensively to treat epilepsy -- and now predicted to help stop protein cell clumping in a rare genetic disorder causing liver disease, according to research by scientists at the University of Pittsburgh School of Medicine.
An article published June 4 on the online Science Express, in advance of publication in the peer-reviewed journal, reported on the effects of the epilepsy drug carbamazepine on mice with a genetic mutation known as alpha-1 antitrypsin deficiency. The deficiency causes the clumping of an abnormal protein that damages liver cells, resulting in scarring and poor liver function.
The deficiency is an inherited disorder that can cause emphysema in adults and liver disease in adults and children. The classic form of the disease affects 1 in 3,000 live births and is the most common genetic cause of children needing a liver transplant. The drug is expected to be tested in adult patients first.
"We will probably get started in the next few months," said the study's senior author David H. Perlmutter, scientific director and physician-in-chief at Children's Hospital of Pittsburgh of UPMC. "This is a drug that has been used so extensively over decades," he said, adding that clinical trials have shown carbamazepine is safe to treat seizures and stabilize mood.
With this drug, instead of massing together, the abnormal protein was consumed by the body, a process called autophagy.
Dr. Perlmutter said that the anti-seizure drug's effect on proteins that clump together was noted in past studies of Huntington's chorea, a genetic disease that leads to dementia.
"It's a terrible disease," he said, and involves a rarer kind of "aggregative protein," but apparently the drug caused the protein to be digested by the body.
He explained the body's cells work to maintain an equilibrium, or balance, and the autophagy process is part of that.
"What's so exciting," he said. "This is a drug that enhances a process that we all have inside us, to protect us every day. Now we can give a drug to stimulate the process."
"The breakthrough here is it's a drug that's safe," Dr. Perlmutter said.
Similar damaging aggregations of proteins, but located in the brain, can be found in Huntington's, Alzheimer's and Parkinson's diseases.
The Pitt researcher is familiar with alpha-1 antitrypsin deficiency, having worked on it for more than 25 years. Although a trial with children takes a lot of work in planning, Dr. Perlmutter said carbamazepine has been given to children for a long time.
"There are a lot of kids who have the disease who are moderately affected. The key question [for a clinical trial] will be finding severely affected children."
Dr. Perlmutter said there is interest among adult liver disease specialists in participating in trials. "This is more common in serious liver disease in adults than most people realize. Seventy adults per year in the U.S. who need a liver transplant get this diagnosis."
One colleague, who sees adult patients with lung disease brought on by the deficiency, said he is encouraged by this and other mouse studies that probe how a familiar drug increases autophagy in the abnormal protein.
"This is exciting," said Dr. James Stoller, a Cleveland Clinic pulmonologist, "It's another wave of investigation for a very vexing clinical problem." Now, he said, there is no treatment for the disease once it damages the liver other than a liver transplant.
"There's a wide appreciation that it's an underrecognized disease. It was only first described in 1963. In a relatively short period of time, progress is being made."
The deficiency affects his patients in their lungs, when as adults they develop emphysema, but they also face a risk for liver disease.
"It's estimated there are at least 100,000 Americans who carry this severe deficiency. Some cases are not recognized," he said, adding that because it runs in families, it is important for people to know if they have it.
Although there is no guarantee that the trial will show benefits to patients, Dr. Perlmutter said the anti-seizure drug has shown to be safe for patients. "We're trying to move this along as fast as possible," he said.
Jill Daly: email@example.com or 412-263-1596.