NEUROBIOLOGY OF EPILEPSY GENES

Project Information

EPITOR

Grant agreement ID: 682345

DOI

10.3030/682345

Project closed

EC signature date 27 September 2016

Start date 1 October 2016

End date 30 September 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 998 760,00

EU contribution

€ 1 998 760,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - EPITOR (NEUROBIOLOGY OF EPILEPSY GENES)

Reporting period: 2021-04-01 to 2022-09-30

Summary of the context and overall objectives of the project

Focal Cortical Dysplasia (FCDs) are malformations of the brain cortical development which manifest with childhood-onset epilepsy and for which treatment often requires epilepsy surgery to control seizures. Nowadays, in the evolving epilepsy surgery population, FCDs represent a growing proportion and thus bring crucial challenges for patient care and treatment.
The project's objectives are to elucidate the genetic etiology of these disorders, decipher the underlying molecular and cellular pathogenic mechanisms using brain tissue obtained from epilepsy surgery and preclinical mouse model, and set up targeted therapeutic strategies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The research project investigates the genetic etiology of focal epilepsies, particularly those associated with Focal Cortical Dysplasia (FCD). The research team has shown that FCDs are caused by brain somatic mutations in genes belonging to the mTOR signaling pathway that occur during brain development. We were able to elucidate the genetic etiology of 30% of FCD1 patients and 60% of FCD2 patients by panel sequencing.
We have generated preclinical mouse models of somatic mutations in DEPDC5 and MTOR genes that recapitulate the main features of the pathology i.e. spontaneous seizures and neuropathological abnormalities.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We discovered the presence of specific features only present in cells carrying the mutations in human FCD brain tissues. We generated preliminary data using molecules administered to preclinical FCD mice that open an exciting therapeutic perspective to treat refractory childhood epilepsies (ERC PoC EpiSen).

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