A scan shows the brain of a man with epilepsy. A newly developed gene therapy targets locations in the brain that are the root of epileptic seizures. Credit: Allison Robbert/The Washington Post/Getty
Three people with epilepsy resistant to drug treatment saw the number of seizures they had per month fall by more than 90% after gene-laden viruses were infused directly into their brains as part of an early-stage clinical trial1.
In each participant, the gene therapy was precisely targeted to a small patch of brain tissue that was the source of their seizures. The viruses carried a gene that makes neurons sensitive to a specific drug, which works like a dimmer switch for the therapy. By combining gene therapy with a drug — an approach known as chemogenetics — researchers can adjust a treatment’s potency, which is not possible with other types of gene therapy. The trial participants did not experience serious side effects.
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The results were reported today in The New England Journal of Medicine by Yang Dai, a neurosurgeon at Xuanwu Hospital of Capital Medical University in Beijing, and his colleagues. “It’s exciting that there’s such a dramatic effect, and that they see very few side effects,” says Matthew Walker, a neurologist at University College London, who was not associated with the study.
But Walker cautions that the study is small. He is also concerned about the long-term use of the drug that participants took after receiving the gene therapy. High doses of the drug, an anti-psychotic called clozapine, have been associated with cardiovascular problems and other negative effects. “In the future, hopefully there are going to be better drugs” for this form of treatment, says Walker, who is the co-founder of the start-up company Focalis Bio in Canterbury, UK, which is also developing gene therapies for epilepsy.
Direct to the brain
The three trial participants were adults with a common form of epilepsy caused by hippocampal sclerosis, a type of scarring in a region of the brain called the hippocampus. The participants had this scarring on only one side of the hippocampus. All three had been diagnosed with epilepsy 10–25 years earlier and had developed resistance to at least two anti-seizure drugs. They also had at least two seizure episodes per month, on average, over the three months before they enrolled in the trial.
The experimental treatment uses a virus called adeno-associated virus 9 to deliver a gene to neurons in the affected area. The gene was engineered to produce proteins specifically in excitatory cells — the ones that are involved in seizures.
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The gene instructs neurons to produce a receptor that binds to clozapine. Clozapine acts like a switch and activates these receptors, reducing the activity of the targeted neurons, the authors say. That reduced activity helps to suppress the abnormal electrical activity that triggers seizures.
Two weeks after receiving the gene therapy during surgery, participants began taking a low dose of clozapine every eight hours. Around two months later, the average number of seizures per month had dropped from 4.5 to 0.5 for two of the participants and from 4 to 0 for the third. Because the study design focused on safety, rather than measuring efficacy, there was no control group.
Walker says that there might be other explanations for the improvement. He adds that it is also not clear whether the effect was because of the combination of gene therapy and clozapine or from one of those components alone.
