Designer receptor technology for the treatment of epilepsy

Epilepsy remains refractory to medical treatment in ~30% of patients despite decades of new drug development. Neurosurgery to remove or disconnect the seizure focus is often curative but frequently contraindicated by risks of irreversible impairment to brain function. Novel therapies are therefore required that better balance seizure suppression against the risks of side effects. Among experimental gene therapies, chemogenetics has the major advantage that the action on the epileptogenic zone can be modulated on demand. Two broad approaches are to use a designer G-protein-coupled receptor or a modified ligand gated ion channel, targeted to specific neurons in the epileptogenic zone using viral vectors and cell-type selective promoters. The receptor can be activated on demand by either an exogenous compound or by pathological levels of extracellular glutamate that occur in epileptogenic tissue. We review the principal designer receptor technologies and their modes of action. We compare the drawbacks and benefits of each designer receptor with particular focus on the drug activators and the potential for clinical translation in epilepsy. •Inhibitory designer receptors (DRs) allow on-demand suppression of seizures upon activation by exogenous drugs or endogenous neurotransmitters.•DRs include modified G-protein coupled receptors, chimaeric ligand-gated ion channels, and mutated non-mammalian channels.•Identification of drug activators of DRs that are already approved for use in humans significantly accelerates clinical translation.