Three adults with drug-resistant epilepsy experienced a reduction of more than 90% in their monthly seizures after researchers injected a gene-carrying virus directly into the brain areas causing their seizures. The early-stage clinical trial used a chemical-genetics approach, in which the gene therapy makes targeted neurons responsive to the drug clozapine, allowing the treatment’s effects to be adjusted. No serious side effects were reported, although researchers caution that the study was small and that long-term use of clozapine carries health risks.
A scan shows the brain of a man with epilepsy. The newly developed gene therapy targets the area of the brain responsible for epileptic seizures. Credit: Alison Robert/Washington Post/Getty
The therapy was precisely targeted at the small regions of brain tissue responsible for seizures in each participant. The virus carries genes that make neurons sensitive to particular drugs, which can act as a dimmer switch for the treatment. By combining gene therapy with drugs—an approach known as chemical genetics—researchers can adjust the treatment’s activity in a way that is not possible with other gene therapies.
The results were reported today in the New England Medical Journal by Yang Dai, a neurosurgeon at Xuanwu Hospital of Capital Medical University in Beijing, and colleagues. “It’s interesting to see such a dramatic effect and so few side effects,” says Matthew Walker, a neurologist at University College London who was not involved in the study.
Walker cautions that the trial included only three people. He is also concerned about the long-term use of clozapine, the antipsychotic drug taken by the participants after gene therapy. High doses of clozapine are associated with cardiovascular disease and other adverse effects.
“My hope is that in the future we’ll develop better drugs for this treatment,” says Walker, co-founder of Focalis Bio, a Canterbury-based start-up that is also developing gene therapy for epilepsy.
Targeting the brain directly
The participants were adults with a common form of epilepsy caused by hippocampal sclerosis, a type of scarring in the hippocampus. Each had scarring on only one side of the hippocampus. They had been diagnosed with epilepsy 10 to 25 years earlier and had developed resistance to at least two anti-seizure drugs. During the three months before entering the trial, each experienced an average of at least two seizures per month.
The experimental treatment uses adeno-associated virus 9 to deliver genes to affected neurons. The gene was designed to produce a protein specifically in excitable cells involved in seizures.
The gene instructs neurons to produce receptors that bind to clozapine. According to the authors, clozapine acts as a switch by activating these receptors and reducing activity in the targeted neurons. This dampens the abnormal electrical activity that causes seizures.
Two weeks after receiving the gene therapy during surgery, the participants began taking low doses of clozapine every eight hours. After about two months, the average number of monthly seizures fell from 4.5 to 0.5 for two participants, and from 4 to zero for the third.
The study had no control group because its design focused on safety rather than measuring efficacy. Walker says there could be another explanation for the improvement, and it remains unclear whether the effect resulted from the combination of gene therapy and clozapine or from either component alone.
Source: www.nature.com
