Closed-loop inhibitory metabotropic glutamate receptor gene therapy for focal refractory epilepsy

Epilepsy is common and frequently refractory to anti-seizure medications. Although ablative surgery is effective when a seizure focus is identifiable, it is only suitable for a minority of patients because of risks of permanent neurological deficit. Several gene therapies for pharmacoresistant focal epilepsy are in development, including tools to achieve neuronal inhibition in response to pathological hyperactivity. Here we show that AAV9-mediated overexpression of the endogenous autoinhibitory metabotropic glutamate receptor mGlu2 (mGluR2, encoded by GRM2) prevents neuronal circuit hyperactivity ex vivo. Overexpression of mGlu2 in the ventral hippocampus suppressed chemoconvulsant-evoked seizures without affecting locomotion or behavioral markers of anxiety in naïve C57BL/6J mice. In a chronic model of pharmacoresistant mesial temporal lobe epilepsy, mGlu2 gene therapy profoundly attenuated spontaneous generalized seizures with no loss of efficacy over 8 weeks, and with concomitant improvements in comorbidities and survival. mGlu2 gene therapy avoids shortcomings of other strategies to suppress pathological hyperactivity in closed loop, relies on a mammalian effector transgene, and may thus be suitable for clinical translation.