BRAINMOS · Brain Mosaicism Matters: Organoids in focus to unveil mechanisms in epileptogenic cortical malformations

Brain Mosaicism Matters: Organoids in focus to unveil mechanisms in epileptogenic cortical malformations

Around 70 million people worldwide are affected by epilepsy, a neurological disorder characterized by recurrent abnormal electrical activity in the brain that causes seizures and substantially impacts their quality of life. In approximately one-third of patients, seizures remain resistant to currently available anti-seizure medications, leaving these individuals at particularly high risk of cognitive and developmental complications. For these patients, invasive epilepsy surgery, involving the removal of the brain region responsible for seizure generation, is often the only therapeutic option. In children undergoing epilepsy surgery, the resected tissue frequently contains developmental brain malformations, with focal cortical dysplasia type II (FCDII) being the most common one. FCDII is characterized by disrupted cortical architecture and the presence of abnormal, enlarged cells. Causative mutations have been identified in some epileptogenic malformations. As such, mutations in mTOR pathway-related genes have been found in more than half of FCDII cases, with the majority displaying mutations in the MTOR kinase itself (57%). Notably, these mutations are typically restricted to a small fraction of brain cells (≤5%) and are absent from the rest of the body, indicating that they arise during early brain development. The cellular and developmental consequences of these somatic mutations remain insufficiently understood. Addressing this challenge requires disease models that accurately recapitulate human brain development and the disease etiology. Although rodent models have provided important insights, they do not fully capture key human-specific features. Human induced pluripotent stem cell (hiPSC)-based systems, including neural cultures and brain organoids, offer increasingly sophisticated platforms for modeling early human neurodevelopment. Several FCDII brain organoid models have recently been established; however, in these models, the mutation is typically present from the earliest stages of development. In contrast, in patients the mutations are thought to arise during early corticogenesis in only a subset of cells, which is likely to influence disease development in fundamentally different ways. Therefore, the BRAINMOS project aims to develop an inducible human stem cell-based FCDII brain organoid model that more accurately reflects the developmental timing and mosaic nature of the disease. By controlling the timing of MTOR mutation induction, the developmental stage–specific effects on cortical development and epileptogenesis can be studied. In this way, the project is expected to generate new mechanistic insights and establish a platform for future therapeutic research in drug-resistant epilepsy.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз