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bioRxiv · 10.1101/2020.08.23.263236

Modeling Genetic Epileptic Encephalopathies using Brain Organoids

Steinberg, D. J.·Saleem, A.·Repudi, S. R.·Banne, E.·Mahajnah, M.·Hanna, J. H.·Carlen, P. L.·Aqeilan, R. I.
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Abstract

Epileptic encephalopathies (EEs) are a group of disorders associated with intractable seizures, brain development and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain-containing oxidoreductase (WWOX) are associated with a relatively mild autosomal-recessive spinocerebellar ataxia-12 (SCAR12) and a more severe early infantile WWOX-related epileptic encephalopathy (WOREE). In this study, we generated an in-vitro model for EEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR-engineered human ES cells and from patient-derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt-pathway and DNA-damage response impairment. Furthermore, we provide a proof-of-concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.

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Steinberg, D. J., Saleem, A., Repudi, S. R., Banne, E., Mahajnah, M., Hanna, J. H., Carlen, P. L., Aqeilan, R. I.. 2020-08-23. Modeling Genetic Epileptic Encephalopathies using Brain Organoids. https://doi.org/10.1101/2020.08.23.263236

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