'Epilepsy in a dish': Stem cell research reveals clues to disease's origins and may aid search for better drugs

A novel stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the disease, and may help in the search for better medicines to treat all kinds of seizure disorders.

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Jack Parent, M.D.

The technique, pioneered by a team of scientists from U-M and the Cleveland Clinic, could be called “epilepsy in a dish”. By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, the team created a miniature testing ground for epilepsy. They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels.

In neurons derived from the cells of children who have a severe, rare genetic form of epilepsy called Dravet syndrome, the researchers reported abnormally high levels of sodium current activity. They saw spontaneous bursts of communication and “hyperexcitability” that could potentially set off seizures. Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity.

The team’s findings differ from what other scientists have seen in mice — demonstrating the importance of studying cells made from human epilepsy patients. Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients’ brains.

“With this technique, we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy,” says team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System. “It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders, and potentially screening medications.”

A platform for testing medications

Many Dravet patients don’t respond to current epilepsy medications, making the search for new options urgent. Their lives are constantly under threat by the risk of SUDEP, sudden unexplained death in epilepsy – and they never outgrow their condition, which delays their development and often requires round-the-clock care.

The team, which also includes Miriam Meisler, Ph.D., a professor in the U-M Department of Human Genetics and Lori Isom, Ph.D., a professor in the U-M Department of Pharmacology, is now working toward screening specific compounds for seizure-calming potential in Dravet syndrome, by testing their impact on the cells in the “epilepsy in a dish” model. The National Institutes of Health has made a library of drugs that have been approved by the U.S. Food and Drug Administration available for researchers to use — potentially allowing older drugs to have a second life treating an entirely different disease from what they were initially intended. Having a U-M team that includes experts in induced pluripotent stem cell biology, sodium channel physiology and epilepsy genetics helps the research progress, Parent notes. “Epilepsy is a complicated brain network disease,” he says. “It takes team-based science to address it."