Silencing excitability of epileptogenic networks in Early Epileptic Disorders – SILENCEED

Cortical malformations are the most frequent causes of drug-resistant childhood epilepsies carrying a lifelong perspective of disability and reduced quality of life. Treatment options for pediatric epilepsies include antiepileptic drugs and surgical removal of epileptogenic brain tissue. However, up to 40% of early epileptic disorders remain resistant to available antiepileptic drugs, and more than 60% of cortical malformations causing drug-resistant epilepsies remain resistant or inaccessible to surgical treatment. Therefore, developing novel therapeutic approaches for drug-resistant epilepsies that could not benefit from pharmacological or surgical treatment is both a challenging and urgent need.
This existing stagnation regarding therapeutic options in pediatric epilepsies are essentially due to the fact that: 1) antiepileptic drugs are developed for treating adult, and not pediatric epilepsies, and mostly empirically; 2) surgical approaches are invasive and inaccessible to most cortical malformations because of their extent, localization, or difficulties in delineating the epileptogenic zone; and, most importantly, 3) there is a crucial lack of relevant preclinical models of early epileptic disorders with cortical malformations.
Our SILENCEED project wants thus to overcome these limitations. We will characterize epilepsy in a novel preclinical model of an epileptogenic cortical malformation that we recently developed. This model is generated by combining RNAi-mediated knockdown and in utero electroporation with a patented tripolar electrode configuration enabling simultaneous transfection of the two brain hemispheres. This model recapitulates several features of a pediatric epilepsy syndrome in terms of genetic cause, anatomo-pathological properties and electro-clinical features, including large and bilateral cortical malformations and spontaneous, early onset seizures.
Using this model, our main objective is to determine if we can silence excitability of epileptogenic brain tissue and prevent/delay epilepsy onset, modify disease progression or mitigate seizures severity. We have already obtained proof-of-concept experiments suggesting that silencing excitability via chronically expressed inward rectifying potassium channels is an efficient strategy for reducing susceptibility to convulsant-induced seizures. We thus have a strong rationale for addressing the hypothesis that silencing excitability of epileptogenic networks in situ, without surgical removal, may ameliorate epilepsy in early epileptic disorders. We will address this question by using several state-of-the-art molecular biological tools enabling conditional, and ‘on demand’ reversible manipulation of neuronal excitability and silencing (tamoxifen and Cre-dependent expression, doxycycline-dependent Tet-on expression, DREADD technology). To characterize epilepsy phenotypes and the potential anti-seizure or disease modifying effects upon suppression of neuronal excitability, we will combine several complementary and integrated approaches, from molecular biology and embryonic brain delivery of transgenes, histopathological analyses of resulting phenotypes, to in vivo recordings in freely behaving or head-restrained anesthetized rodents with single or multi-electrodes.
Given the existing stagnation regarding therapeutic options to treat early epileptic disorders, we hope that the SILENCEED project will ultimately translate into novel treatment strategies, less invasive than surgery and more efficient than currently available antiepileptic drugs.