Children with Dravet syndrome, a severe form of epilepsy that begins in years of age, are at high risk of sudden unexpected death in epilepsy (SUDEP) and can also develop intellectual disability and autism. These therapies may not alleviate these symptoms.
A group of scientists at Gladstone Institutes led by Dr. Ennart Mucke has released new findings in the journalScience Translational Medicine that could guide the development of better therapeutic therapies for Dravet syndrome.
In a mouse model of Dravet syndrome, researchers determined that genetically removing the protein tau from the entire body during embryonic development reduces epilepsy, SUDEP, and autism-like behaviors. In the first study, they identified the key cell type in the brain in which tau levels must be decreased to avoid these problems. Moreover, they also demonstrate that decreasing tau is still effective in mice when the intervention is delayed until after their birth.
A team of scientists headed by Mucke (left) and including Eric Shao (center) and Che-Wei Chang (right) discovered a promising treatment strategy for the protein tau, which might be beneficial for Dravet syndrome, epilepsy, autism, and Alzheimer''s disease.
According to Mucke, the researchers at the Gladstone Institute of Neurological Disease, our findings provide insight into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain. 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 is a promising therapeutic target non only for Dravet syndrome, but also for a variety of other conditions, including various kinds of epilepsy and some forms of autism, as well as Alzheimers disease and related neurodegenerative disorders.
Pinpointing the Crucial Brain Cells
The correct balance between excitatory and inhibitory neurons is crucial for a well-functioning brain, which is resulting in an abnormally high and synchronized activity in brain cells that are susceptible to seizures and other symptoms.
Mucke and his colleagues have recently shown that leaving tau from the whole brain alters the activity of both excitatory and inhibitory neurons, although in different ways. The present study aimed to establish whether or not tau is more important to avoid.
In the Dravet mouse model, scientists used genetic tools to eliminate tau selectively from one or the other cell type. They found that eliminating tau from excitatory neurons reduced disease manifestations, whereas eliminating tau from inhibitive neurons did not.
According to Mucke, who is also the Distinguished Professor of Neuroscience and a professor of neurology at University of San Francisco, tau production in excitatory neurons sets the stage for all of these abnormalities to occur, including autistic behaviors, epilepsy, and unexpected death.
Initiating Treatment after Birth
The techniques employed by the scientists to remove tau from specific cell types are effective and precise, but they aren''t yet easy to exploit as a therapeutic therapeutic approach in humans. So, the researchers decided to adopt a more powerful approach: global tau reduction in the brain with DNA fragments known as antisense oligonucleotides. The researchers found that most Dravet syndrome symptoms were gone four months later.
SUDEP, seizure activity, and repetitive behaviors have been significantly reduced, according to Eric Shao, PhD, a scientist at the Muckes lab and the first author.
ASO therapy had no obvious side effects.
Researchers from Gladstone found that worldwide reducing tau in the brain with an ASO reduced the most symptoms of Dravet syndrome. Here, Shao examines sections of the mouse brain to see if the anti-tau ASO penetrated all areas of the brain.
We are particularly pleased about these findings, especially since a Phase I clinical trial in Alzheimers patients has already begun, according to Mucke. It may be helpful to consider this approach as well for Dravet syndrome and related ailments. However, selecting the appropriate date for treatment initiation will be crucial, as the opportunity to succeed may be quite short.
Although Alzheimers disease, epilepsy, and autism are often linked to abnormally high levels of excitatory and inhibitory neuronal activities, this condition might be fixed by tau-lowering therapy.
Despite the fact that therapy based on anti-tau ASOs would involve repeated spinal taps, something most people would rather avoid. Mucke is partnering with Takeda Pharmaceuticals to develop small molecules that might reduce brain tau levels when administered as a tablet.