PROJECT: JTC2017: KARTLE

Temporal lobe epilepsy (TLE) is the most common form of human epilepsy and a major health burden, as forty percent of TLE patients are refractory to currently available pharmacotherapies. The overarching hypothesis of this project is that ectopic synaptic kainate receptors (KARs) in the dentate gyrus (DG) markedly contribute to epileptiform activity in patients with TLE, implying that ectopic KARs represent a promising new therapeutic target for TLE displaying pharmacoresistance. The central goal of the project is thus to design and validate two parallel strategies to target aberrant synaptic KARs, i.e., newly devised pharmacological agents and cell-directed viral gene delivery vectors. More specifically, we will identify and characterize novel pharmacological agents selectively targeting KARs composed of the GluK2/GluK5 subunits. Concurrently, we will develop original gene transfer/therapy tools to silence KARs in DG cells, based on Adeno-associated viruses (AAV) and RNA interference (RNAi). The novel pharmacological agents and the AAV/RNAi gene therapy vectors will first be tested in cellular systems and in small animal models of TLE, prior to their comprehensive validation in human hippocampal tissues obtained from surgically resected human hippocampus. Thereby, we will extend pre-clinic studies in animal models to pathophysiologically most relevant human epileptic tissue, which should pave the way for future clinical translation of our innovative approaches.