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HEIndividual fellowship2024–2026

Epi-Stop · Recapitulating and preventing epileptogenesis in early human brain network development

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2024-04-01 → 2026-03-31
EU contribution
€183,601
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

Recapitulating and preventing epileptogenesis in early human brain network development

Epilepsy affects tens of millions of people worldwide, and around one in three patients does not respond to existing anti-seizure medicines. A major reason is that current drugs treat the symptoms, the seizures, rather than preventing the underlying disease process by which a healthy brain network becomes epileptic. That process, called epileptogenesis, often begins very early in development, before any seizure occurs, which makes it extremely difficult to study in people. Tuberous Sclerosis Complex (TSC) is a genetic condition and a leading cause of childhood drug-resistant epilepsy. Because TSC has a known genetic cause and the epilepsy frequently begins in infancy, it offers a valuable window onto how epilepsy first develops in the human brain. Until now, however, there has been no good way to observe this earliest, prenatal stage of human epileptogenesis in the laboratory. The Epi-Stop project set out to close that gap using human cerebral organoids - three-dimensional models of early brain tissue grown from human stem cells. The overall aim was to build a TSC organoid model that reproduces the early electrical changes seen in patients, to understand the biological mechanism that drives those changes, and to test whether the disease process can be stopped before it takes hold. The project pursued three objectives: to identify the electrical signatures of developing epilepsy in the model, to uncover the cellular and molecular changes responsible, and to test whether specific drugs applied at a critical developmental window can prevent the pathology from emerging.

Data: CORDIS, © European Union

Project objective

Epilepsy is one of the most common neurological disorders, yet current treatments fail to prevent seizures in more than a third of cases (~37%). Most drug targets focus on seizure suppression; however, these are symptoms of abnormal developmental changes in the neural network. The processes that give rise to epileptic brain regions are summarized by the concept of epileptogenesis. Therefore, preventing epileptogenesis is critical for long-lasting seizure freedom. Studying epileptogenesis is challenging, as the developmental processes involved in it occur before birth during neurodevelopment itself. Recent progress in stem cell models, however, has the potential to change this. The Knoblich Lab pioneered the use of human cerebral organoids to model disease in-vitro, such as Tuberous Sclerosis (TSC). Cortical tubers are the source of drug-resistant epilepsy (DRE) in TSC, which our recent study (Eichmüller et al., Science 2022) uncovered to originate from a specific precursor cell type; CLIP cells. Strong preliminary evidence shows that pathological processes are occurring in TSC organoids which recapitulate epileptogenic electrical biomarkers called high frequency oscillations (HFOs).In this proposal I will utilise our brain organoid model to understand human circuit-level dysfunction in epilepsy and identifyevidence-based causal treatment for epileptogenesis prevention. Therefore, I plan to classify stages of epileptogenesis in human brain TSC organoids using large-scale signal features and in-depth molecular characterizations to identify biomarkers for abnormal circuit initiation and progression. I will reveal stage-specific druggable targets for epileptogenesis and then test novel anti-epileptogenic compounds on pathological network activity prevention. Together, this project marks a change in the approach towards epileptic drug discovery to combat the significant socioeconomic burden of drug-resistant epilepsy.

Original text from CORDIS.

Participants

  • INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienCoordinatorAustria

Links

Data: CORDIS, © European Union