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

Abstract

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
Volume13
Issue number8
DOIs
StatePublished - 9 Aug 2021

Bibliographical note

Funding Information:
We would like to thank all members of the Aqeilan?s laboratory for fruitful discussion and Jonathan Monin for his invaluable bioinformatic analysis. We are grateful to Dr. Abed Nasereddin and Dr. Idit Shiff from the Genomic Core Facility for their help. We would also like to thank Prof. Eli Pikarsky from the Hebrew University for his guidance in the histological analysis, and Dr. Jonathan Bayerl and Dr. Venkat Raghavan Krishnaswamy from Weizmann Institute of Science for their support in stem cells and organoid cultures. The Aqeilan?s laboratory is funded by the European Research Council (ERC) [No. 682118] and Proof-of-Concept ERC Grant [No. 957543]. Shani Stern is supported by the Zuckerman STEM Leadership Program.

Funding Information:
We would like to thank all members of the Aqeilan’s laboratory for fruitful discussion and Jonathan Monin for his invaluable bioinformatic analysis. We are grateful to Dr. Abed Nasereddin and Dr. Idit Shiff from the Genomic Core Facility for their help. We would also like to thank Prof. Eli Pikarsky from the Hebrew University for his guidance in the histological analysis, and Dr. Jonathan Bayerl and Dr. Venkat Raghavan Krishnaswamy from Weizmann Institute of Science for their support in stem cells and organoid cultures. The Aqeilan’s laboratory is funded by the European Research Council (ERC) [No. 682118] and Proof‐of‐Concept ERC Grant [No. 957543]. Shani Stern is supported by the Zuckerman STEM Leadership Program.

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

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