Gene Therapy Reduces Seizures by 90% in Epilepsy Clinical Trial

Three adults whose epilepsy had resisted at least two anti-seizure medications saw their monthly seizures fall by more than 90% after surgeons infused gene-laden viruses directly into the scarred tissue of their brains, Nature reported. The results, published this week in The New England Journal of Medicine by Yang Dai, a neurosurgeon at Xuanwu Hospital of Capital Medical University in Beijing, and his colleagues, represent a dramatic response in an early-stage clinical trial of gene therapy for the brain.

The participants all suffered from a common form of epilepsy caused by hippocampal sclerosis, a type of scarring confined to only one side of the hippocampus. Each had been diagnosed with epilepsy 10 to 25 years earlier and had developed resistance to at least two anti-seizure drugs. In the three months before enrolling in the trial, participants averaged at least two seizures per month—a rate that met the criteria for the experimental treatment and showed that standard drugs had not controlled their seizures.

Rather than performing surgery to remove the damaged tissue, the research team used adeno-associated virus 9 as a delivery vehicle, infusing the virus directly into the small patch of brain tissue that was the source of the seizures. The virus carried a gene engineered to produce proteins specifically in excitatory cells—the neurons that drive seizure activity. Once inside these cells, the gene instructed them to manufacture a receptor that binds to clozapine, an anti-psychotic drug. When the patients take clozapine, it acts like a switch, activating the engineered receptors and reducing the activity of the targeted neurons, which helps suppress the abnormal electrical activity that triggers seizures.

This combination of gene therapy and medication—an approach known as chemogenetics—gives researchers the ability to adjust a treatment’s potency after the fact, a flexibility not possible with other types of gene therapy. The viruses delivered the genetic instructions precisely to the affected area, leaving the rest of the brain untouched. All three trial participants completed the treatment without experiencing serious side effects, a safety outcome that drew immediate attention from the neurology community.

“It’s exciting that there’s such a dramatic effect, and that they see very few side effects,” said Matthew Walker, a neurologist at University College London who was not associated with the study.

Walker, who is also the co-founder of the start-up company Focalis Bio in Canterbury, UK, which is developing its own gene therapies for epilepsy, cautioned that the study remains small, involving only three people. He also raised concerns about the long-term use of the drug that participants took after receiving the gene therapy. High doses of clozapine have been associated with cardiovascular problems and other negative effects, a risk that becomes significant when the medication must be taken indefinitely to maintain seizure control.

“In the future, hopefully there are going to be better drugs” for this form of treatment, Walker said.

The trial builds on broader advances in gene therapy for neurological conditions, but the addition of the drug-controlled mechanism distinguishes this approach from previous attempts. By combining the targeted gene delivery with clozapine, the researchers created a system where the therapy can be adjusted like a dimmer switch, dialing the neurons’ activity up or down depending on the patient’s needs. For people whose seizures persist despite multiple medications, this offers a potential alternative to the invasive surgery traditionally used to remove seizing brain tissue.

The findings contribute to growing evidence that genetic therapies offer new hope against incurable brain diseases. They also move the field closer to brain editing that is closer to reality, where gene-altering tools tackle deadly disorders at their neurological source. Yet the reliance on clozapine means the treatment is not yet ready for widespread clinical use. The participants will need to continue taking the drug to keep their seizures suppressed, and researchers must develop safer pharmaceutical alternatives before the therapy can advance beyond early-stage trials.

For the three patients, each of whom had lived with uncontrollable seizures for a decade or more despite trying multiple drugs, the reduction of more than 90% represents a level of relief that medication never achieved. Whether that quiet can be sustained long-term without exposing patients to the cardiovascular risks of clozapine remains the central question that the next phase of research must answer.