First-in-Human Study of Chemogenetic Therapy GA002 for Refractory Epilepsy Published in NEJM

This study evaluated the preliminary safety, feasibility, and clinical efficacy of GA002 in three patients with unilateral hippocampal sclerosis-associated mesial temporal lobe epilepsy (MTLE-HS). During the two-month efficacy assessment period, the mean monthly seizure frequency decreased from 4.33 to 0.33 episodes, representing a 92.59% reduction. Corresponding changes were also observed in electroencephalography (EEG), ¹⁸F-FDG PET, and quality of life metrics. All subjects are currently undergoing long-term safety follow-up.

Epilepsy, commonly known as “sheep madness,” is a common neurological disorder caused by “abnormal discharges” of brain nerve cells. There are approximately 50 million epilepsy patients worldwide, and about one-third of them still cannot achieve adequate seizure control despite treatment with existing anti-epileptic drugs. For patients with clearly identified lesions, resection or ablation of the epileptogenic focus can provide benefits. However, when the lesion involves critical functional areas, poses high surgical risks, or presents other limitations, there remains a significant unmet clinical need.

Chemogenetic neuromodulation offers an alternative approach: target neurons are first engineered to express designer receptors via gene delivery, and then small-molecule drugs are used to modulate the activity of these receptors, thereby achieving pharmacological control over the activity of the relevant neurons. This technique has previously been primarily employed in basic and preclinical neuroscience research. The present study systematically applies this strategy to humans for the first time, providing direct human evidence for its clinical translation.

Scientific Basis and Drug Development History of GA002: The chemogenetics technology involved in the GA002 drug was first reported and applied by Bryan Roth’s team in 2007. In 2013, Minmin Luo’s team first applied chemogenetics using adeno-associated virus (AAV) as a vector for the precise modulation of neural circuits (specifically, the regulation of feeding behavior). Since its establishment in 2022, GenAns Biotech has initiated projects to develop precision modulatory drugs primarily based on chemogenetics for the treatment of refractory epilepsy and other intractable brain disorders, while independently developing precise drug delivery devices and medical solutions. In 2024, the first patient was dosed in an Investigator-Initiated Trial (IIT). In 2026, the company obtained Investigational New Drug (IND) approvals in both China and the United States, and administered the first dose in the registrational clinical trial in September of that year.

This investigator-initiated trial (IIT, ChiCTR2500111157) represents the first complete validation in humans of the chemogenetic regulatory closed-loop system termed “install the switch–activate the switch.” The study enrolled a total of three patients diagnosed with unilateral mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) confirmed by imaging and electrophysiological assessments.

• Gene Delivery: GA002 is an adeno-associated virus (AAV) vector carrying the hM4D(Gi) gene regulated by the CaMKIIα promoter. Under intraoperative MRI monitoring, the research team employed convection-enhanced delivery (CED) to precisely infuse GA002 into the head, body, and tail of the hippocampus on the lesional side, achieving uniform distribution within the target area.

• Target Coverage: Intraoperative MRI demonstrated adequate coverage of the hippocampal head, body, and tail, with no observed reflux into the ventricles or subarachnoid space.

• Pharmacological activation: Starting two weeks postoperatively, patients orally administered low-dose clozapine daily to maintain hM4D(Gi) receptor activation.

• Endpoint Assessment: The study designated safety as the primary endpoint, with seizure frequency, seizure severity, epileptiform discharges on electroencephalogram (EEG), ¹⁸F-FDG PET metabolism, and quality of life serving as secondary endpoints. Relevant efficacy outcomes were evaluated by blinded assessors.

This marks the first human clinical application of chemogenetics technology worldwide, signifying that this regulatory approach, which originated from basic research, has officially transitioned from animal experiments to the stage of clinical validation.

During the 8–12-month follow-up period, two patients remained seizure-free; one additional patient experienced an increase in seizures during an unintended interruption of clozapine therapy, with seizures brought back under control upon resumption of treatment. In this first-in-human study with a sample size of only three patients, although this “withdrawal–rechallenge” observation alone cannot definitively prove efficacy, the direction of change is consistent with the mechanistic characteristics of chemogenetics, which relies on pharmacological activation and reversible modulation.