Using Induced Pluripotent Stem Cells (iPSCs) to Study Ion Channel Mutations that Cause Dravet Syndrome
Jack M. Parent, MD: Dravet Syndrome Foundation Medical Advisor
Dr. Parent is an associate professor of neurology, director of the Neurodevelopment and Regeneration Laboratory, and co-director of the Comprehensive Epilepsy Center in the University of Michigan Medical School.
Dravet syndrome is caused by mutations in a voltage-gated sodium channel. How these mutations alter brain cell function and lead to severe epilepsy and developmental problems is unknown. Ion channel abnormalities are often studied in tissue culture so that the “cells in a dish” can be directly manipulated and examined. It has been difficult to study the mutated ion channels in Dravet Syndrome, however, because they come from a very large gene that makes a large and unwieldy protein. Several laboratories have made tissue culture cells that have sodium channels with Dravet mutations using non-neuronal (non-brain) cells with very mixed results. It is likely that such cells do not show the full effects of the mutation because they are not brain cells and also do not have the overall genetic properties present in patients’ cells.
To overcome this problem, we are using a new advance in stem cell biology known as the induced pluripotent stem cell (iPSC) method. First discovered in 2006, this technique allows one to reprogram any type of immature or adult cell into a stem cell. The stem cells then may be directed to form any tissue of the body in order to study diseases of specific tissues. To apply this approach for studying Dravet Syndrome, we take skin biopsies from patients and reprogram the skin cells to turn them into stem cells. We then direct the stem cells to from brain cells. The advantages are that the cells carrying the disease-causing mutation are the patient’s own brain cells, which carry the specific genetic background of the patient and represent the specific types of cells affected by the disease. We are using this approach to examine how the mutation alters brain cell function, and eventually to screen new treatments that will correct the disorder. Thus, a long-term goal of this work is to develop individualized, patient-specific therapies for Dravet Syndrome and eventually other epileptic disorders.
Jack M. Parent, MD1, Lori L. Isom, PhD2, Miriam H. Meisler, PhD3, Departments of 1Neurology, 2Pharmacology and 3Human Genetics, University of Michigan Medical Center, Ann Arbor, Michigan.
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