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Brain-heart connection: U-M scientists take on deadly epilepsy with new $3.3M grant

Stem cell & heart research in Dravet syndrome aims to fight sudden death risk

ANN ARBOR, Mich. — For children and adults with epilepsy, the possibility of dying suddenly and without warning looms in the background all the time – yet scientists and doctors still don’t know why it occurs.

Now, researchers from the University of Michigan Medical School and colleagues around the nation will try to get to the heart of this mystery, and perhaps find new ways to spot those most at risk. A new $3.3 million grant will help fuel the U-M work.

The U-M team believes that the answer for some epilepsy patients may actually lie in the heart, its connection to the brain, and genetic defects that occur in cells of both organs. By studying those cells, they hope to find out exactly what’s going on.

They’ll explore the heart-brain connection with the new five-year grant, announced today by the National Institutes of Health. Their work will use heart cells from animals, and brain and heart cells made from human “adult” stem cells.

epilepsy stem cells
These heart cells made from “adult” stem cells derived from a patient’s skin have been carefully stained to show which cells are destined to become part of a ventricle (green), and which will become part of an atrium (red). This kind of details helps scientists understand what’s going wrong in the cells.

The stem cells actually started out as skin cells donated by patients with Dravet syndrome, a severe form of childhood epilepsy – so they carry the genetic defect that causes that disease. That defect, which affects electrical activity between cells, occurs in both heart and brain cells.

The U-M team’s grant, from the National Institute of Neurological Diseases and Stroke, is part of a new Center Without Walls that involves scientists in nine groups around the country. All the teams will work on different aspects of SUDEP, or sudden death in epilepsy, and share their results with one another in person and online.

SUDEP kills one in every 1,000 people with any form of epilepsy each year, most of them between the ages of 20 and 40. For children, teens and young adults with Dravet syndrome, the rate is even higher.

“SUDEP is the most devastating complication of epilepsy, and we’re only now understanding how common it is,” says Jack Parent, M.D., a neurologist who co-directs the U-M Health System’s Comprehensive Epilepsy Program and co-leads the U-M SUDEP team. “Many of the researchers in this center have lost patients to SUDEP. This funding will mobilize us to make inroads into this terrible problem.”

Lori Isom, Ph.D., the co-lead of the new project and interim chair of the U-M Department of Pharmacology, notes that the Center Without Walls funding approach will especially help the U-M team, because their focus straddles two different organs. They hope to find biomarkers, or detectable signs in heart rhythms or brain waves, that can act as a warning sign for a high potential of SUDEP and guide treatment.

Plus, the grant will help them work with researchers led by Doug Nordli, M.D., at the Lurie Children’s Hospital at Northwestern University, which has a large clinical program for Dravet syndrome and will look at heart rhythm activity during and after seizures in its patients as part of the study. 

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 – and they never outgrow their condition, which delays their development and often requires round-the-clock monitoring and care.

Isom’s work on this project to date has focused on mouse heart cells that carry the same genetic defect as patients with Dravet syndrome. Her lab is capable of measuring changes in electrical activity in the membranes of those cells, and has already done the same with nerve cells made from stem cells. Since the mouse heart is different from the human heart in important ways, the team also hopes to develop a strain of rabbit that has the same genetic vulnerability as Dravet patients.

SUDEP lab
U-M postdoctoral research fellow Chad Frasier, Ph.D., with advanced equipment that can detect electrical activity within the membranes of single cells – important for studying epilepsy at the most basic level.

Parent and his team in the Department of Neurology have focused on deriving and studying neural stem cells from skin cells – a technique called induced pluripotent stem cell derivation. They will continue this work with cells from Lurie patients as part of the study, and grow heart cells as well as neurons from stem cells derived from skin.

Isom notes that Dravet families have begun to come to scientific research meetings, to learn about the latest findings, and attend grief counseling sessions to help them cope with the loss of their children. The sorrow she sees among these families, and the idea of putting a child to bed not knowing if they will ever wake up, helps motivate her research, she says.

Other U-M researchers will partner on the research, including Jose Jalife, M.D. Todd  Herron, Ph.D., and Omar Berenfeld, Ph.D., from the U-M Center for Arrhythmia Research, and pediatric cardiologist David Bradley, M.D. Another pediatric cardiologist, Mark Russell, M.D., and Parent are also involved in the Sudden Death in the Young Registry, a collaboration between the National Institutes of Health and the Centers for Disease and Control and Prevention.

In addition to the new NINDS grant and other NINDS funding, the team has support from donors including AV Fuel of Ann Arbor and the Dravet Syndrome Foundation. The U-M Center for Organogenesis and Citizens United for Research in Epilepsy provided seed funding for the new initiative.

For more on previous stem cell work on Dravet syndrome by Parent, Isom and others at U-M, see this article: http://umhealth.me/epidish

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