Recapitulating and preventing epileptogenesis in early human brain network development

Informazioni relative al progetto

Epi-Stop

ID dell’accordo di sovvenzione: 101155338

DOI

10.3030/101155338

Progetto chiuso

Data della firma CE 6 Marzo 2024

Data di avvio 1 Aprile 2024

Data di completamento 31 Marzo 2026

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 183 600,96

Coordinato da

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Austria

Periodic Reporting for period 1 - Epi-Stop (Recapitulating and preventing epileptogenesis in early human brain network development)

Periodo di rendicontazione: 2024-04-01 al 2026-03-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Working with patient-derived stem cell lines and matched healthy control lines, the project grew TSC and control organoids and recorded their electrical activity repeatedly over several months of development. A custom open-source software pipeline was built to detect and characterise high-frequency oscillations - a specific electrical pattern that clinicians use to locate epilepsy-causing tissue in patients. The same analysis was applied both to the organoid recordings and to clinical recordings from patients, allowing a direct comparison between model and human disease.

To identify the cells responsible, the project labelled and recorded from a particular class of inhibitory nerve cell that arises during a defined stage of development, combining electrical recordings, single-cell measurements of cell properties, and detailed imaging of cell structure. Finally, the project tested several clinically relevant compounds, applied over the long term during the critical developmental window, to see whether they could prevent the disease signature from appearing.

The project successfully built a human organoid model that reproduces, in the laboratory, the same electrical biomarker used clinically to identify epilepsy-causing tissue in TSC patients. The electrical signatures that emerge in the TSC organoids closely match key features of those recorded from patients, establishing the model as a faithful and tractable system for studying the earliest stages of human epileptogenesis.

The project identified a specific developmental subtype of inhibitory nerve cell as a driver of the abnormal network synchronisation that underlies the epileptic signature. It further showed that this cell population is over-produced in TSC organoids and that reducing it lessens the abnormal activity.
Most importantly, the project demonstrated that long-term inhibition of a particular cell-signalling pathway, applied during the critical developmental window, prevents the epileptic phenotype from emerging - both in terms of electrical activity and of the underlying changes in cell structure and number. To the project's knowledge, this is the first demonstration of pharmacological prevention of epileptogenesis in a human laboratory model.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Epi-Stop moves the study of genetic epilepsy beyond seizure suppression toward genuine prevention. By recreating early human epileptogenesis in a dish and showing it can be interrupted, the project offers a mechanism-based route to intervening before epilepsy becomes established - a fundamentally different therapeutic strategy from today's symptom-focused medicines.

The potential impact is significant given the scale of unmet need in drug-resistant epilepsy, which affects around one in three epilepsy patients. Because the cell-signalling pathway identified can be targeted with drugs that are already approved for other medical uses, the findings point toward a repurposing-friendly path to a future clinical-trial concept for preventive treatment in children with TSC who are at risk but not yet symptomatic.

Realising this potential will require further work: confirmation of the findings in complementary models, refinement of the timing and safety of preventive treatment, and engagement with clinical partners and patient organisations to design a trial concept. To support uptake by the wider research and clinical community, the project's validated organoid model, open-source analysis software, shared experimental protocols and cell lines, and open-access publication are all designed to lower the barrier for others to build on the work. The underlying approach also contributes to European priorities in health and in open, digital, FAIR-compliant research.