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

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.