Scientists have unearthed a way of preventing a severe form of epilepsy in children called Dravet syndrome. By removing a protein in the brain called tau, they lowered the chances of having a seizure and developing an intellectual disability.
People with Dravet syndrome develop the condition when they’re infants and have seizures for the rest of their lives. This happens because there is an imbalance between excitatory and inhibitory neurons in the brain. Shifting the balance towards excitation results in over-firing of neurons and abnormally high brain activity. Having a seizure early in life increases the risk of dying and autism.
Prior research on Dravet syndrome reveals that mice that had the tau protein genetically removed from their brains during embryonic development had a lower chance of epilepsy, death, and autism-like behavior. The current study expands on the findings by studying what cell type helps Dravet syndrome symptoms when tau is removed.
“Our findings provide new insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain,” says Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease in a press release. “They are also encouraging from a therapeutic perspective, since in humans, initiating treatment after birth is still more feasible than treating embryos in the womb.”
Tau has been a target for neurological disorders beyond Dravet syndrome. If successful, the treatment could help other types of epilepsy and neurodegenerative disorders such as Alzheimer’s disease.
The team used genetic tools to selectively remove tau protein in a mouse model of Dravet syndrome without affecting other cells. When tau was taken out of excitatory neurons, mice were less likely to show symptoms of Dravet syndrome. In contrast, taking tau out of inhibitory neurons had no effect.
“This means that tau production in excitatory neurons sets the stage for all these abnormalities to occur, including autistic behaviors, epilepsy, and sudden unexpected death,” says Dr. Mucke.
While the experiment took tau out of specific cell types, this is difficult to do in humans. Therefore, the researchers opted to remove all tau proteins from the brain altogether using DNA fragments called antisense oligonucleotides (ASO). Ten days after birth, the researchers administered anti-tau ASO to mice’s brains. Four months later, they observed that most Dravet syndrome symptoms were gone with no obvious side effects.
“We observed a robust reduction of SUDEP, seizure activity, and repetitive behaviors,” says Eric Shao, PhD, a scientist in Mucke’s lab and the first author of the study.
Dr. Mucke adds: “We are excited about these findings, especially since another anti-tau ASO has already undergone a Phase I clinical trial in people with Alzheimer’s disease,” says Mucke. “It could be useful to consider this strategy also for Dravet syndrome and related conditions. However, defining the optimal timing for treatment initiation will be key, as the window of opportunity might be quite narrow.”
Since delivering anti-tau ASOs in humans would require many painful spinal tap procedures, the team is working on a pill that would deliver small molecules to lower brain tau levels.
The study is published in the journal Science Translation Medicine.