Modeling genetic epileptic encephalopathies using brain organoids

Daniel J. Steinberg, Srinivasarao Repudi, Afifa Saleem, Irina Kustanovich, Sergey Viukov, Baraa Abudiab, Ehud Banne, Muhammad Mahajnah, Jacob H. Hanna, Shani Stern, Peter L. Carlen, Rami I. Aqeilan

Research output: Contribution to journalArticlepeer-review


Developmental and epileptic encephalopathies (DEE) 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 DEEs, 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.

Original languageEnglish
Article numbere13610
JournalEMBO Molecular Medicine
Issue number8
StatePublished - 9 Aug 2021

Bibliographical note

Publisher Copyright:
©2021 The Authors. Published under the terms of the CC BY 4.0 license


  • DNA damage
  • SCAR12
  • WOREE syndrome
  • Wnt pathway
  • cerebral organoids

ASJC Scopus subject areas

  • Molecular Medicine


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