U. MICHIGAN (US) — Using stem cells, researchers have created a miniature testing ground for epilepsy, an advance that could help in the search for better medicines to treat all kinds of seizure disorders.
For the study, researchers turned skin cells of epilepsy patients into stem cells, and were then able to turn those stem cells into neurons, or brain nerve cells. 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 report 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.
To make the induced neurons used in the epilepsy study, the scientists took skin cells from patients with Dravet syndrome and from healthy comparison volunteers. They then coaxed these cells to become induced pluripotent stem cells, and then from there grew them in conditions that make them grow into neurons—brain nerve cells. (Credit: U. Michigan)
The new findings differs 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 techinique, we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy,” says senior author and team leader Jack M. Parent, professor of neurology at the University of Michigan.
“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.”
Published in the journal Annals of Neurology, Parent and colleagues report striking discoveries about what is happening at the cell level in the neurons of Dravet syndrome patients with a mutated SCN1A gene.
They also demonstrate that the effect is rooted in something that happens after function of the gene is reduced due to the mutation, though they don’t yet know how or why the nerve cells overcompensate for partial loss of this channel.
And, they found that the neurons didn’t show the telltale signs of hyperexcitability in the first few weeks after they were made—consistent with the fact that children with Dravet syndrome often don’t suffer their first seizures until they are several months old.
“In addition, reproduction of the hyperactivity of epileptic neurons in these cell cultures demonstrates that there is an intrinsic change in the neurons that does not depend on input from circuits in the brain,” says co-author Miriam Meisler, distinguished university professor of human genetics.
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 the condition, which delays development and often requires round-the-clock care.
“Working with patient families, and translating our sodium channel research to a pediatric disease, has made our basic science work much more immediate and critical,” says Lori Isom, professor of pharmacology and of molecular and integrative physiology.
The team 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 US 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.
The researchers hope to identify drugs that affect certain aspects of sodium channels, to see if they can dampen the sodium currents and calm hyperexcitability. The team is exploring new techniques that can make this process faster, using microelectrodes and calcium-sensitive dyes and also hope to use the model to study potential drugs for non-genetic forms of epilepsy.
The work is funded in part by the National Institutes of Health, the American Epilepsy Society, the Epilepsy Foundation.
Source: University of Michigan