Novel therapeutic strategies to prevent cognitive impairment in pharmacoresistant epilepsy


CALL: 2014

DOMAIN: BM - Life Sciences, Biology and Medicine




INDUSTRY / PPP PARTNER: University of Luxembourg


KEYWORDS: Epilepsy; Dravet syndrome; Cognitive impairment; Antiepileptic drugs

START: 2014-11-01

END: 2018-10-31


Submitted Abstract

Dravet syndrome (DS), also called severe myoclonic epilepsy of infancy (SMEI), is one of the most frequent form of pharmacoresistant epilepsy. More than 40 antiseizure drugs (ASDs) have been approved, but still about 30% of epilepsy patients do not respond to any of these ASDs, including Dravet syndrome patients. Approximately 80% of DS patients have de novo mutations in SCN1A, which encodes the Nav1.1 sodium channel alpha subunit. The mortality rate is 15-20% in children. An important hallmark of DS is that most patients have to cope with the disease but also with many additional medical problems that may be associated with epilepsy. Indeed, apart from psychiatric disorders as depression and anxiety, many patients suffer from impaired cognitive performance caused either by the disease itself and/or by the side effects of the medications prescribed.Recent studies on zebrafish have demonstrated its ability to be a promising in vivo model for biomedical research. The zebrafish and human genomes share high homology – for example, 85% of the known epilepsy genes in humans are found in the zebrafish genome. In this view, the zebrafish is becoming a relevant genetic model organism for human DS.This project has focused on the cognitive functions of zebrafish DS models in order to find similarities between cognitive impairments in human patients and our zebrafish model. We also exposed zebrafish and mouse DS models to ASDs and novel antiseizure compounds known to suppress seizures in various models and found several of them being active in our models. Furthermore, we have discovered a potential, never-explored before, mechanism of action leading to this antiseizure activity.Our discoveries during this PhD project have led to 2 follow-up projects: (1) further investigation of the drug candidates in a mouse model of DS, and (2) establishment of a clinical trial for one compound.

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