Credit: Pascal Goetgheluck/Science Source
Chemogenetics shows promise for treating epilepsy in pilot trial
A chemogenetic therapy has shown promise for treating epilepsy that does not respond to drug treatment (New Engl. J. Med. 2026 DOI: 10.1056/NEJMc2606815). The three-patient study is the first time that researchers have used designer receptors, commonly referred to as DREADDs, to change the activity of an adult’s brain.
The trial is one of at least seven testing DREADDs in humans in China, news of which stunned researchers at a US National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative meeting in August. Although the new results come from a pilot study rather than a formal clinical trial, neuroscientists call its hints at safety and efficacy exciting.
“It certainly has caused a lot of excitement in the field,” says Dimitri Kullmann, a neurologist at University College London who was not involved in the study. Basic scientists have wondered for years about using chemogenetics—introducing an engineered protein that responds to an otherwise inactive companion drug—to treat brain diseases. But when it comes to starting human tests, Kullmann says, the cost and complexity of the potential treatment have gotten in the way.
The origins of the trial idea
Minmin Luo, director of the Chinese Institute for Brain Research, Beijing, and a senior author on the paper, has used chemogenetic approaches to alter specific neural circuits’ activity in his research laboratory for well over a decade. On a visit to Xuanwu Hospital in Beijing, he was surprised to hear that the best treatment for certain types of epilepsy is to remove or destroy the part of the brain where seizures begin. He says that using designer receptors to tamp down those cells’ activity instead seemed like an obvious approach to him.
Luo struck up a collaboration with Xuanwu’s president, physician Guoguang Zhou. “At the beginning, he was a little bit skeptical,” Luo says. But after a mouse model showed early promise, the project picked up steam.
The study team worked with Luo’s company, GenAns Biotechnology, to package an inhibitory receptor in a suitable viral vector and optimize the dosage in animals. Vector design and viral dose are key decisions in gene therapy, neuroscientist Michael Michaelides of the US National Institute on Drug Abuse, who was not involved in the trial, tells C&EN—and getting them right is a huge cost driver.
“At the beginning, I think scientists like me felt like, ‘Why haven’t we tried it in humans yet?’ ” Luo says. “Once we get to this point, we can understand.”
Finally, a team of physicians operated on the first of three men whose epilepsy had not responded to any available drugs. They introduced a virus carrying an inhibitory receptor to his hippocampus, where his seizures began. After he recovered from the surgery without serious incident, the man began to take a very low dose of the psychiatric drug clozapine, which should lower the activity of neurons expressing the new receptor.
The study’s key endpoint was safety, not efficacy—but all three study participants reported fewer seizures after receiving the chemogenetic therapy. One of them had an unplanned interruption in taking clozapine. He had two breakthrough seizures while he was off the drug, and none after he got back on it.
More studies are needed, and some have already started
Several neuroscientists that C&EN spoke to say that although that isn’t a conclusive demonstration that the drug-receptor combination controls his seizures, it is an interesting hint. According to Jon Willie, a neurosurgeon at the University of Texas at Austin who operates on people with severe epilepsy, research that includes a study arm without the companion drug is especially important because “in the short term, just poking the hippocampus is going to cause a reduction in seizure frequency and severity.”
Several of the neuroscientists that C&EN spoke to for this story say that they would like to see a control arm in future studies, and some controlled studies have already begun. GenAns has a Phase 1 study underway in China, and it received regulatory approval last week to launch a Phase 1 in the US. Other companies are planning their own early-stage chemogenetics trials elsewhere in the world, and basic scientists are eyeing applications for other types of disease.
Yasmin Hurd, chair of translational neuroscience at Icahn School of Medicine at Mount Sinai, says the study “raises the possibility of eventually translating such approaches into circuit-selective psychiatric therapeutics” for problems like mood and substance-use disorders. But first, she says, researchers will need more proof of the approach’s safety and effect, and ideally a companion drug more inert than clozapine.
Luo agrees that more work will be needed. But he says, “At this point, it’s more than 1 year for these three patients. I think all three have become seizure-free. That’s quite encouraging.”