Early intervention in a mouse model of Dravet Syndrome prevented onset of critical disease symptoms.
For children with Dravet Syndrome, day-to-day life presents many stressors such as epileptic seizures, sleeping challenges, cognitive dysfunction, and a risk for premature mortality. Researchers at Stanford University want to alter the course of this devastating illness with a new drug that stimulates the underperforming neurons responsible for these symptoms: interneurons.
Interneurons play a critical role in receiving, processing, and transmitting information throughout the nervous system. In healthy humans, interneurons interpret sensory information and regulate motor activity, but in Dravet Syndrome, interneuron firing is disrupted, resulting in the severe symptoms that characterize the disease. Most cases of Dravet Syndrome arise from a mutation in the sodium voltage-gated channel alpha subunit 1 (Scn1a) gene that decreases the expression of an interneuron-specific protein subunit, Nav1.1, which is critical for electrical activity in the brain.
Feng Gu, a neuroscientist at Stanford University, and his team recently reported in Proceedings of the National Academy of Sciences that tropomyosin receptor kinase B (TrkB), which bypasses Scn1a and increases expression of Nav1.1, is a promising drug target for patients with Dravet Syndrome (1). They treated mice carrying the same mutation as patients with Dravet Syndrome with a TrkB agonist just before they were old enough to develop seizures. Mice treated with the agonist had significantly fewer seizures and lived longer than untreated mice.
“The most surprising [thing] is the drastic reduction in seizures and increase in survival with only seven days of treatment,” said Horacio de la Iglesia, a neuroscientist at the University of Washington, who was not involved in the study.
In mutant mice treated with the TrkB agonist, the density of synapses between interneurons increased, and the inhibitory transmission necessary to prevent seizures improved. Gu’s team observed increased expression of the sodium channel protein necessary for interneuron firing, which countered the effect of the Scn1a mutation. Mutation-carrying mice treated with the TrkB agonist were 77% less likely to die than untreated mutant mice.
In control mice, “this drug boosted the inhibitory side of the equation by causing maybe sprouting of the interneurons of the inhibitory cells, which leads to an interesting question as to whether it would work in any kind of disorder — even one where the inhibitory neurons were not being affected — because it boosts their health and their action significantly,” said David Prince, a neuroscientist at Stanford Medicine and the principal author of the study.
Prince and Gu next plan to conduct longer studies to further characterize the drug and to look for potential off-target effects.
“The best traits [of the study] are the endpoint results, which are the reduction of seizures and the reduction of mortality,” Iglesia said. “At the end of it, what we want is, of course, to save the lives of Dravet patients as much as we can.”
References
- Gu, F. et al. Chronic partial TrkB activation reduces seizures and mortality in a mouse model of Dravet syndrome. PNAS 119, e2022726119 (2022).
