Abstract: Epilepsy is a major cause of morbidity, mortality, and disability. To date, there are no medications that can prevent or halt the progression of epilepsy. Recently, many genetic causes of epilepsy have been identified, providing insights into pathways involved in epileptogenesis. Mutations causing hyperactivity of the mTOR pathway (so-called “mTORpathies”) have emerged as an important cause of cerebral malformations and epilepsy. One such mTORopathy is polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, which is caused by a homozygous loss-of-function in the STRADA gene. We seek to determine the effect of STRADA mutations on early cortical development and on neuronal function. We employ patient-derived and genetically edited human stem cells to form human cortical organoids, 3-D neural structures that resemble the developing fetal cortex. At early stages, PMSE patient-derived organoids display larger size and a budding phenotype, with an increased number of regions of ventricular-zone-like rosettes. At later stages, patient-derived organoids display an increase in HOPX expression, a marker for outer radial glia, a cell type that results the expansion of the human cortex. Together, these findings may explain the megalencephaly seen in PMSE patients. Studies are underway to assay neuronal function in the organoids.
