Tau: A New Way To Treat Autism and Epilepsy

Tau: A New Way To Treat Autism and Epilepsy ...

Children with Dravet syndrome, a severe form of epilepsy that starts in adulthood, are at high risk of sudden unexpected death in epilepsy (SUDEP) and may also develop intellectual disability and autism. Certain therapies may, however, be difficult to improve.

A group of scientists at Gladstone Institutes led by Dr. Jennart Mucke have released new information in the journal Science Translational Medicine that could guide the development of better therapeutic strategies for Dravet syndrome.

In a mouse model of Dravet syndrome, researchers discovered that genetically removing the protein tau from the whole body during embryonic development reduced epilepsy, SUDEP, and autism-like behaviors. In a new study, they identify the key cell type in the brain in which tau levels must be reduced to avoid these limitations. Additionally, they demonstrate that decreasing tau is still effective in mice when the intervention is delayed until after their birth.

A team of scientists led by Mucke (left) and including Eric Shao (right) and Che-Wei Chang discovered a promising treatment strategy aimed at the protein tau, which might be beneficial for Dravet syndrome, epilepsy, autism, and Alzheimer''s disease.

According to Mucke, the physiotherapist of the Gladstone Institute of Neurological Disease, our findings give insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain. They are also helpful from a therapeutic perspective, since in humans, initiating therapy after birth is still more feasible than treating embryos in the womb.

Tau is a promising therapeutic goal non only for Dravet syndrome, but also for a wide range of other conditions, such as 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 inhibiting neurons is essential for developing a healthy brain, while the latter enhances the capacity of other neurons. Dravet syndrome also causes an abnormally high and synchronized activity in brain tissues that can manifest as seizures and other symptoms.

Mucke and his colleagues have recently demonstrated that removing tau from the whole brain alters the activities of both excitatory and inhibitory neurons, although in different ways. The present study aimed to determine whether reducing tau in excitatory or inhibitory neurons is more important.

The scientists compared tau to those found in an excitatory neurons but not using artificial intelligence.

This means that tau production in excitatory neurons sets the stage for all of these abnormalities to occur, including autistic behaviors, epilepsy, and unexpected death, according to Mucke, who is also the Distinguished Professor of Neuroscience at UC San Francisco.

Initiating Treatment after Birth

The experimental techniques employed by the scientists to remove tau from specific cell types are effective and precise, but they are not yet easy to implement as a therapeutic therapy in humans. So, the team decided to adopt a more acceptable approach: global tau reduction in the brain with DNA fragments known as antisense oligonucleotides, or ASOs. The scientists then injected an anti-tau ASO into mice''s brain 10 days after birth and discovered that most symptoms of Dravet syndrome were gone four months

According to Eric Shao, a PhD student at the Muckes lab and the first author, we observed a sharp reduction of SUDEP, seizure activity, and repetitive behaviors.

ASO therapy also had no obvious side effects.

Researchers at Gladstone discovered that globally reducing tau in the brain with an ASO reduced the majority of Dravet syndrome symptoms. Here, Shao examines sections of the mouse brain to see if the anti-tau ASO penetrated all areas of the brain.

A second anti-tau ASO has started a Phase I clinical study in people with Alzheimers disease, according to Mucke. However, it might be beneficial to consider this strategy equally for Dravet syndrome and related illnesses. However, defining the appropriate timing for treatment initiation will be crucial.

Although Alzheimers disease, epilepsy, and autism have many causes, they all seem to be associated with abnormally high levels between excitatory and inhibitory neuronal activities, and this possibility may be resolved with tau-lowering therapies.

In the end, a treatment based on anti-tau ASOs would involve repeated spinal taps, something that most people would rather avoid. Mucke is working with Takeda Pharmaceuticals to develop small molecules that might reduce brain tau levels when administered as a tablet.

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