Epilepsy research strengthens case for new gene therapy for Dravet syndrome

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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 the survival of people with the disease.

The gene therapy, developed by Stoke Therapeutics, is currently undergoing clinical trials. Since most cases of Dravet syndrome are caused by a mutation in the SCN1A gene, leading to a reduction in SCN1A protein production, the new approach is designed to stimulate the production of SCN1A at normal levels. If successful, the approach, called Targeted Augmentation of Nuclear Gene Production, or TANGO, would be the first treatment for the root cause of the disease, a lack of this particular protein in specialized brain cells.

The new research – by UVA’s Manoj K. Patel, PhD, and Eric R. Wengert, PhD, and their collaborators – demonstrates how experimental therapy restores healthy cell function and reduces seizures in mice from laboratory.

“Our results show that a single treatment with the TANGO approach in infant mice completely prevented the seizures and premature death typically seen in our mouse model of Dravet syndrome,” said Patel, from the Department of Anesthesiology at the UVA. “Furthermore, our study provides the first evidence that TANGO treatment actually targets and rescues the physiological alteration of a 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 usually appears in babies and young children. Patients have frequent and prolonged seizures; behavior problems; developmental delays; movement and balance problems; and other issues. People with the disease often require constant care and face an increased risk of sudden death. It is thought to affect around 1 in 15,700 people.

Existing treatments for Dravet syndrome include medication, vagus nerve stimulation, and adopting an extremely low-carb ketogenic diet. But none of the treatments directly address the underlying cause of the disease, the missing protein in nerve cells called interneurons. Stoke’s gene therapy aims to change that by tricking the gene responsible for the protein into increasing its production.

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

The results, say the researchers, suggest that gene therapy directly addresses the underlying cause of the disease. Although findings in mice don’t always hold true in humans, the results bode well as human testing continues. The results also suggest that the approach may be useful in the treatment of other forms of epilepsy caused by mutations in the SCN1A gene, UVA scientists say.

“It can be difficult for patients with Dravet syndrome to find good treatment options because many conventional treatments often fail to completely 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 continue to help many people. These results bring us one step closer. more of this reality.”

Once TANGO clinical trials are complete, the therapy will need to be approved by the federal Food and Drug Administration before it can be made available to patients.

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