First Human Trials of Chemogenetics: Drug-Controlled Genetic Modulation of Neurons

The first trials of drug-controlled genetic modulation target specific brain regions, while precise cell-type selection remains the next challenge

In the August review of the first trials using engineered DREADD receptors, chemogenetics already appeared to be moving from a laboratory tool into clinical use. After gene delivery, cells produce the receptor, and clozapine changes their activity. A review published on 2 September 2026 explains more precisely how the system selects cells. Surgery determines the target location in the brain, but selective targeting of neuronal types within that location still needs to be developed.

Chemogenetics works in two steps. An AAV viral vector delivers the gene for hM4Di, an engineered receptor that reduces neuronal activity, to a selected brain region. The cells produce this receptor. Clozapine then binds to it and reduces their activity. The drug dose can be used to control the magnitude of the effect. The effect stops after clozapine is withdrawn, although the cells continue to produce the receptor.

In the Parkinson’s disease protocol, AAV carrying hM4Di is injected at defined coordinates into both subthalamic nuclei, which are deep structures in the brain’s motor circuits. The hSyn promoter, a DNA sequence that initiates receptor production, is broadly active in neurons within this region. Surgery defines the anatomical target, so different neuronal types within that target produce the receptor. In the neuropathic pain protocol that is currently recruiting participants, hM4Di is delivered to the anterior cingulate cortex, a region involved in pain processing, after which the clozapine dose is adjusted.

In epilepsy, a seizure focus may contain excessive excitation in a specific location. The focus contains both excitatory and inhibitory neurons. The next engineering challenge is to develop promoters that activate receptor production in the required cell type. This could, for example, allow inhibitory neurons to be activated to reduce excessive excitation.

Drug selection is the second part of the design. Clozapine binds to hM4Di at a low dose, but it also acts on the brain’s endogenous receptors. In an experiment with GRANPA, a modified version of hM4Di, the receptor was activated with the antihistamine diphenhydramine. In mice, this receptor and drug pair reversibly altered the activity of the selected circuit and reduced seizure severity. Delivery is the third challenge. AAV is injected directly into the brain, so the current method requires neurosurgery.

The review identifies three goals for the next version: selecting specific cell types within a region, finding a more selective receptor and drug pair, and making delivery less invasive.