Epilepsy research boosts case for new gene therapy for Dravet syndrome


Date:
January 19, 2022
Source:
University of Virginia Health System
Summary:
New research suggests how a newly developed gene therapy can treat
Dravet syndrome, a severe form of epilepsy, and potentially prolong
survival for people with the condition.



FULL STORY ========================================================================== Research from the University of Virginia School of Medicine suggests how
a newly developed gene therapy can treat Dravet syndrome, a severe form of epilepsy, and potentially prolong survival for people with the condition.


==========================================================================
The gene therapy, developed by Stoke Therapeutics, is now in clinical
trials.

Because most Dravet syndrome cases are caused by a mutation in the SCN1A
gene, resulting in a reduction in SCN1A protein production, the novel
approach is designed to boost production of SCN1Ato normal levels. If successful, the approach, called Targeted Augmentation of Nuclear Gene
Output, or TANGO, would be the first treatment for the fundamental
cause of the disease, a lack of this particular protein in specialized
brain cells.

The new research -- from UVA's Manoj K. Patel, PhD, and Eric R. Wengert,
PhD, and their collaborators -- demonstrates how the experimental therapy restores the cells' proper function and reduces seizures in lab mice.

"Our results show that a single treatment with the TANGO approach into
infant mice completely prevented seizures and the premature death
typically seen in our mouse model of Dravet syndrome," said Patel,
of UVA's Department of Anesthesiology. "Further, our study provides
the first evidence that TANGO treatment actually targets and rescues
the physiological impairment of one group of brain cells known to cause seizures in Dravet syndrome." TANGO for Dravet Syndrome Dravet syndrome
is a rare but serious form of epilepsy that typically first appears in
babies and young children. Patients have frequent, prolonged seizures; behavioral issues; developmental delays; movement and balance issues;
and other problems. People with the condition often require constant
care and face an increased risk of sudden death. It is thought to affect approximately 1 in 15,700 individuals.

Existing treatments for Dravet syndrome include medications, vagus nerve stimulation and the adoption of an extremely low-carb ketogenic diet. But
none of the treatments directly addresses the underlying cause of the
disease, the missing protein in nerve cells called interneurons. Stoke's
gene therapy aims to change that by prompting the gene responsible for
the protein to increase production.

Patel and his team wanted to see what effect restoring the missing protein might have on the interneurons' activity. Working with a mouse model of
Dravet syndrome, they found that a single treatment with the TANGO therapy rescued the deficits in the interneurons and made them behave like those
that naturally had the full amount of the protein. The interneurons,
which function to constrain the brain's excitability and protect against seizures, became more responsive, more active, and better able to do
their jobs. As a result, the TANGO treatment decreased seizures, and
the Dravet syndrome mice lived longer.

The results, the researchers say, suggest that the gene therapy is
directly addressing the underlying cause of the disease. While mouse
findings do not always hold true in humans, the results bode well as
human testing continues.

The findings also suggest that the approach may be useful in treating
other forms of epilepsy caused by mutations in the SCN1A gene, the UVA scientists say.

"It can be difficult for patients with Dravet syndrome to find good
treatment options, as many conventional treatments often fail to fully
block seizures and prevent sudden death," Wengert said. "This process
of developing and validating gene therapy approaches that directly
address the core mechanism of genetic epilepsy syndromes is exciting
work that we hope will go on to help many people. These results take us
one step closer to that reality." After the TANGO clinical trials are complete, the therapy would need approval from the federal Food and Drug Administration before it could become available to patients.

special promotion Explore the latest scientific research on sleep and
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University_of_Virginia_Health_System. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Eric R. Wengert, Pravin K. Wagley, Samantha M. Strohm, Nuha Reza,
Ian C.

Wenker, Ronald P. Gaykema, Anne Christiansen, Gene Liau, Manoj
K. Patel.

Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a
rescues parvalbumin interneuron excitability and reduces seizures
in a mouse model of Dravet Syndrome. Brain Research, 2022; 1775:
147743 DOI: 10.1016/j.brainres.2021.147743 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220119090848.htm

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