Focus on a new treatment for autism and epilepsy

SAN FRANCISCO, Calif. – April 27, 2022 – Children with Dravet syndrome, a severe form of epilepsy that begins in infancy, experience seizures, usually lifelong. They are at high risk of Sudden Unexpected Death in Epilepsy (SUDEP) and may also develop intellectual disability and autism. Available treatments usually fail to improve these symptoms.

Now, a group of Gladstone Institutes scientists led by Lennart Mucke, MD, are reporting new findings in the journal Science Translational Medicine that could guide the development of better treatment strategies for Dravet syndrome and related conditions.

Researchers have previously found, in a mouse model of Dravet syndrome, that genetic removal of tau from the whole body during embryonic development reduces epilepsy, SUDEP and autism-like behaviors. In the new study, they identify the key cell type in the brain in which tau levels must be reduced to avoid these problems. They also show that tau lowering is still effective in mice when the intervention is delayed after they are born.

“Our findings provide new insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain,” says Mucke, director of the Gladstone Institute of Neurological Disease. “They are also encouraging from a therapeutic point of view, because in humans, initiating treatment after birth is even more feasible than treating embryos in the womb.”

Tau is a promising therapeutic target not only for Dravet syndrome, but also for a variety of other conditions, including different types of epilepsy and some forms of autism, as well as Alzheimer’s disease and related neurodegenerative disorders. .

Identify crucial brain cells

A well-functioning brain depends on the right balance between the activity of excitatory and inhibitory neurons – the former stimulate the activity of other neurons, while the latter suppress it. Dravet syndrome causes an imbalance between these cell types, resulting in abnormally high and synchronized activity in brain networks that can manifest as seizures and other symptoms.

Mucke and colleagues recently showed that removing tau from the whole brain alters the activities of excitatory and inhibitory neurons, albeit in different ways. The current study aimed to determine whether it is more important to reduce tau protein in excitatory or inhibitory neurons.

To do this, the scientists used genetic tools to selectively knock out tau from one or another cell type in the Dravet mouse model. They found that removal of tau from excitatory neurons reduced disease manifestations, while removal of tau from inhibitory neurons did not.

“This means that tau production in excitatory neurons sets the stage for all of these abnormalities to occur, including autistic behaviors, epilepsy, and sudden and unexpected death,” says Mucke, who is also Joseph B Professor Emeritus. Martin of Neuroscience and Professor of Neurology at UC San Francisco.

Start treatment after birth

Although the genetic approaches used by scientists to eliminate tau from specific cell types are effective and precise, they are not yet easy to use as a therapeutic intervention in humans. So the team turned to a more practical option: global reduction of tau in the brain with DNA fragments known as antisense oligonucleotides, or ASOs. Scientists administered anti-tau ASO into the brains of mice 10 days after birth and found that most symptoms of Dravet syndrome disappeared 4 months later.

“We observed a robust reduction in SUDEP, seizure activity, and repetitive behaviors,” says Eric Shao, PhD, scientist in Mucke’s lab and first author of the study.

Moreover, the ASO treatment had no obvious side effects.

“We are excited about these findings, especially since another anti-tau ASO has already been tested in a Phase I clinical trial in people with Alzheimer’s disease,” says Mucke. “It might be useful to consider this strategy also for Dravet syndrome and related conditions. However, defining the optimal time for the start of treatment will be essential, as the window of opportunity could be quite narrow.

Although Alzheimer’s disease, epilepsy and autism have diverse causes, they all appear to be associated with abnormally high ratios between excitatory and inhibitory neural activities – and this abnormality could potentially be corrected by therapies that lower the tau.

Yet treatment based on anti-tau ASOs would involve repeated lumbar punctures, a procedure most people prefer to avoid. Therefore, Mucke is partnering with Takeda Pharmaceuticals to develop small molecules that could reduce tau levels in the brain when given in pill form.

/Public release. This material from the original organization/authors may be ad hoc in nature, edited for clarity, style and length. The views and opinions expressed are those of the author or authors. See in full here.

About Antoine L. Cassell

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