Engineered alpha-7 nicotinic acetylcholine receptor-glycine receptor chimeric ion channel (PSAM-GlyR)

The engineered chemogenetic chloride-conducting ion channel encoded by KRIYA-382 is a synthetic chimeric receptor designed for the precise control of neuronal activity in the treatment of focal epilepsy. This target consists of a modified ligand-binding domain from the alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) fused to the chloride-selective pore of a glycine receptor (GlyR). It is specifically engineered to be activated by varenicline, a CNS-penetrant small molecule originally approved for smoking cessation. When varenicline is administered, it binds to the expressed channel in the epileptic focus, triggering the influx of chloride ions and subsequent hyperpolarization of the target neurons. This mechanism effectively inhibits the hyperexcitability responsible for seizure generation. As a component of a one-time gene therapy, this channel provides a regulatable therapeutic approach, allowing clinicians to modulate neuronal inhibition through the pharmacological administration of an oral ligand.

Other names

Varenicline-gated chloride channelChemogenetic inhibitory ion channelPSAM4-GlyRAlpha7-GlyR chimeraPharmacologically selective actuator module-glycine receptor

Varenicline acts as a selective agonist for the engineered chimeric channel; upon binding, the channel opens to allow the influx of chloride ions, which hyperpolarizes the neuron and suppresses action potential firing.