The objective of this study was to determine if lowering the expression of the Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GRIK2) using RNA interference can be a therapeutic strategy for temporal lobe epilepsy (TLE).

We created an AAV9-vector carrying two miRNAs under the control of a neuron-specific promotor targeting GRIK2 (AMT-260). The vector has been tested in a pilocarpine mouse model for TLE and assessed for safety in non-human primates (NHP). Additionally, hippocampal organotypic slices from TLE patients were treated with AMT-260. The efficacy of AMT-260 was measured in the mouse model using electroencephalogram (EEG) and behavior as readouts, and in hippocampal organotypic slices using electrophysiological recordings. The safety and biodistribution of AMT-260 was assessed in NHP after 1 month of treatment.

AMT-260 showed a dose-dependent decrease in electrical seizures and hyperlocomotion and improved health. A full biological effect was observed at 5.0E+09 vg per hippocampus. Organotypic slices from patients with TLE treated with AMT-260 showed a decrease in the number of electrical seizures. Convection enhanced, MRI guided intrahippocampal delivery in NHP resulted in local high copies of vector and miRNA expression with substantial knockdown of GRIK2, but with no adverse findings and limited peripheral exposure to the vector.

AMT-260 shows an excellent preclinical and safety profile and will proceed into clinical testing to treat patients with refractory mesial temporal lobe epilepsy.