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Prestigious ERA-NET Grant for Boyan Bonev

MOSAIC to pave the way towards new targeted therapies for childhood drug-resistant epilepsy.

Epilepsy is one of the most frequent neurological diseases characterized by recurrent unprovoked epileptic seizures. In Europe alone, it affects ~1% of the population, corresponding to about 7.5 million patient and amongst them, focal epilepsies, as found in Focal Cortical Dysplasia (FCD), are the most frequent type, accounting for two-thirds of cases.

FCD occur during embryogenesis as the result of abnormal migration and differentiation of neurons and manifests in young children as recurrent focal seizures, that are often resistant to currently used antiepileptic drugs and not accessible even by the most cutting-edge surgical techniques. The treatment of FCD-related epilepsies therefore represents a major medical challenge and is in urgent need for novel targeted therapies.

To overcome these limitations and to build a sound, scientific foundation for developing novel FCD therapies, Boyan Bonev teamed up with Stéphanie Baulac (Paris Brain Institute, France) and De­nis Jabaudon (University of Geneva, Switzerland) to understand the molecular and circuit bases of cortical malformation and epileptogenesis in FCD using in vitro and in vivo approaches. The endeavor will mainly focus on mutations in the mTOR (mechanistic target of rapamycin) pathway since those have been reported as an underlying cause of FCD, but with so far unclear etiology in a substantial fraction of patients.

Receiving 900 000 € from the ERA-NET Neu­ron, the MO­SAIC project will assess the molecular causes of FCD by combining high-throughput genomic and epigenomic CRISPR screens, single-cell transcriptomics as well as in vivo mapping of circuit activity and patient-derived cerebral organoids for functional proof-of-concept rescue approaches. Here, the Bonev lab will lead the efforts on the high-throughput screening by a) designing a custom-guide RNA library targeting all genes and neuronal cis-regulatory elements, b) performing an in vivo screen for mismigration and mTOR activity and c) providing computational analysis for identifying candidate genes and cis-regulatory elements suitable for follow-up analyses within MOSAIC.

The overall goal of this multidisciplinary research program is to establish a genetic diagnosis for the onset of FCD by creating roadmap of the molecular mechanisms leading to the emergence of the disease. This will finally pinpoint potentially druggable targets for more effective therapeutic intervention for childhood drug-resistant epilepsy.

ERA-NET NEURON, the Network of European Funding for Neuroscience Research, is an international consortium of 27 research funding organizations and ministries from 23 countries. It provides a “platform focused on brain-related diseases and disorders of the nervous system and holds a strategic position in bringing pre-clinical and clinical research communities closer together and fostering translational research, while covering the entire value chain”. In the 2021 joint call, 18 multinational research consortia were selected for funding on the topic of ‘Neurodevelopmental Disorders’ with a total funding volume of about 19.2 M€.

(Text: Helmholtz Pioneer Campus, HPC)