Background

Over 30% of all epilepsy patients suffer from drug-resistant epilepsy, where seizures are not controlled despite taking multiple anticonvulsants. Frequent seizures accumulate damage to neural networks and disrupt patients' daily lives. In current clinical practice, surgical resection of the seizure focus has been considered when drugs fail. The issue is that the brain tissue triggering seizures is often adjacent to critical cortex governing language, memory, or motor functions. Extensive resection of brain lesions carries the risk of irreversible neurological deficits, such as permanent language impairment or hemiplegia.

For patients where surgical resection is impossible, electrical neuromodulation devices like Deep Brain Stimulation (DBS) or Responsive Neurostimulation (RNS) have been proposed as alternatives. However, these device implantations require invasive electrode placement and battery replacement surgeries, and they face limitations in precisely managing only target neurons because the current diffuses indiscriminately into surrounding neural networks. This is why a precision therapy that selectively inhibits only abnormal neurons triggering seizures, without physically damaging normal neural networks, was desperately needed.

Key Findings

Researchers announced clinical results applying chemogenetics technology—which expresses inhibitory artificial receptors in desired neurons—to brain lesions in refractory epilepsy patients. The method involves loading a DREADD (Designer Receptor Exclusively Activated by Designer Drugs) gene into an inactivated Adeno-Associated Virus (AAV) vector and precisely injecting it into the seizure focus via stereotactic neurosurgery. The introduced artificial receptor is the hM4Di protein, a modified muscarinic receptor that transmits inhibitory signals within the cell. This receptor does not react at all to natural neurotransmitters in the brain, such as dopamine or glutamate.

Instead, it is designed to react selectively with Deschloroclozapine (DCZ), a specific chemical ligand administered externally. In practice, when the inducing drug DCZ was administered orally to patients, the electrical activity of neurons in the hyperactive seizure focus showed a stable sedative trend for several hours. In intracranial EEG tests, a clear pattern of a more than 70% decrease in the frequency of pathological brainwave discharges compared to baseline was observed. Notably, the absence of neurological side effects such as systemic paralysis or cognitive decline, which had been a particular concern, is an encouraging result in terms of safety. This confirms that a molecular switch, which selectively turns off neural circuits only upon oral drug administration without physically cutting brain tissue, operates safely within the human brain.

Significance and Outlook

This achievement represents a significant clinical milestone in expanding chemogenetics, which had long remained in laboratory animal research, into the actual treatment area for human central nervous system diseases. It has opened a circuit-specific treatment pathway that fully preserves brain function for refractory patients who did not respond to existing drug therapies and were ineligible for surgery. Because it acts only on target cells, it can also reduce the burden of cognitive impairment or systemic toxicity associated with high-dose drug administration.

The application potential is not limited to epilepsy. It is evaluated that the same platform can be applied to various central nervous system disorders, such as Parkinson's disease, neuropathic chronic pain, and refractory psychiatric conditions, which are caused by hyperexcitation of abnormal neural circuits. There are clear challenges to be addressed for commercialization. Long-term follow-up observation is required to confirm whether the artificial genes carried by the viral vector are stably maintained in human brain tissue for several years without immune rejection. Large-scale follow-up clinical trials are also identified as essential tasks to verify whether desensitization occurs, in which artificial receptors become less sensitive upon repeated drug administration.