Kainate Receptors as a Target for Gene Therapy in Focal Cortical Dysplasia – KARE-Dysplasia

Focal cortical Dysplasia (FCD) is one of the major causes of focal onset seizures refractory to antiepileptic drugs (AEDs). Only one-third of these patients are eligible for epilepsy surgery (i.e. the removal of the epileptogenic area), which offers the chance of seizure remission for 30%-40% of patients. There is a clear need to develop new and more efficient therapy.
Gene therapy constitutes a promising alternative to conventional therapies as it can be applied focally using appropriate viral vectors and is less invasive than surgical resection, likely reducing undesirable changes in brain function. Various ongoing preclinical projects currently investigate the benefits of therapies aimed at increasing the expression of inhibitory peptides or ion channels or using chemogenetic compounds for the treatment of epilepsy. In this project we propose a different strategy, aimed at reducing the expression of kainate receptors (GluK2-containing KARs), a subclass of glutamate receptors involved in epileptogenesis, through local viral transduction of selective miRNAs. One of the main advantages of miRNAs is that it locally inhibits specific neuronal proteins without altering the genetic code. In a preclinical project, we recently proved that this strategy was efficient in reducing epileptiform events in temporal lobe epilepsy without affecting normal synaptic transmission (Boileau et al, under review). The aim of our project, supported by preliminary data, is to evaluate if the GluK2-containing KAR miRNA strategy can be proposed for treating focal cortical epilepsies and, more specifically, type II FCD.