Focal cortical dysplasia (FCD) is a rare, genetic, non-syndromic developmental malformation of the cerebral cortex that accounts for 5-10% of patients with focal epilepsy, and that represents the main cause of pharmaco-resistant epilepsy. FCD affects mainly children and young adults, and nowadays the only treatment available is invasive surgical resection of the brain epileptogenic zone, which is effective in only 62% of cases. Thus, a better understanding of the disorder is urgent in order to point towards strategies that would allow to generate new, more effective and less invasive treatments.
Among FCD subtypes, FCD type 2 (FCD2) is characterized at the histopathological level by an abnormal structure of the cortex in the area affected by the disorder, where the characteristic six-layer structure appears disrupted. Abnormally large (cytomegalic) cells are also a classic hallmark of FCD2. Around 60% of FCD2 cases are due to inherited germline and/or de novo somatic mutations in genes regulating the mechanistic target of rapamycin (mTOR) pathway, which regulates cell growth, metabolism and proliferation. These mutations always cause a hyperactivation of the mTOR pathway that is thought to be associated with the aforementioned hallmarks of the disorder. Together with its focal nature, the role of somatic mutations in causing the disorder has recently defined FCD as a mosaic disorder of the brain. Despite these findings, a clear understanding of the consequences of mTOR pathway mutations, and especially mosaic mutations, in the development of the cerebral cortex and the insurgence of the disorder is still missing.
This project addressed the genetic, cellular and molecular mechanisms underlying the pathophysiology of FCD2 by modeling the disorder in vitro using 3-dimensional culture systems called cortical organoids that are generated from patient-derived human induced pluripotent stem cells (hiPSCs). This system has the advantage of reproducing developmental features specific to humans, and thus overcomes existing limitations encountered in mouse models, where the disorder is only partially reproducible.
