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

doi:10.15252/emmm.202013610

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

Department of Neurobiology

Research output: Contribution to journal › Article › peer-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 language	English
Article number	e13610
Pages (from-to)	e13610
Journal	EMBO Molecular Medicine
Volume	13
Issue number	8
DOIs	https://doi.org/10.15252/emmm.202013610
State	Published - 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

Access to Document

10.15252/emmm.202013610

Cite this

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title = "Modeling genetic epileptic encephalopathies using brain organoids",

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.",

keywords = "DNA damage, SCAR12, WOREE syndrome, Wnt pathway, cerebral organoids",

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

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{\textquoteright}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{\textquoteright}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: {\textcopyright}2021 The Authors. Published under the terms of the CC BY 4.0 license",

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AU - Repudi, Srinivasarao

AU - Saleem, Afifa

AU - Kustanovich, Irina

AU - Viukov, Sergey

AU - Abudiab, Baraa

AU - Banne, Ehud

AU - Mahajnah, Muhammad

AU - Hanna, Jacob H.

AU - Stern, Shani

AU - Carlen, Peter L.

AU - Aqeilan, Rami I.

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N2 - 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.

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Modeling genetic epileptic encephalopathies using brain organoids

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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