Project: Targeting aberrant KAinate Receptors in Temporal Lobe Epilepsy

Acronym KARTLE
Duration 30/04/2019 - 30/04/2020
Project Topic 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.
Network NEURON Cofund
Call Call for Proposals for Research Projects on "Synaptic Dysfunction in Disorders of the Central Nervous System"

Project partner

Number Name Role Country
1 National Center for Scientific Research Coordinator France
2 National Institute of Health and Medical Research Partner France
3 Heidelberg University Hospital Partner Germany
4 Centre Interdisciplinaire de Recherche sur le Médicament (CIRM), Université de Liège, Belgique Partner Belgium