Modeling genetic epileptic encephalopathies using brain organoids.
Daniel J Steinberg1, Srinivasarao Repudi1, Afifa Saleem2,3
1The Concern Foundation Laboratories, Department of Immunology and Cancer Research-IMRIC, The Lautenberg Center for Immunology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
EMBO Molecular Medicine
|July 16, 2021
Summary
This study models severe infantile epileptic encephalopathies using brain organoids. Researchers identified key brain abnormalities and demonstrated potential rescue by restoring WW domain-containing oxidoreductase (WWOX) function.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Developmental and epileptic encephalopathies (DEE) are severe neurological disorders characterized by intractable seizures and impaired brain development.
- Mutations in the tumor suppressor WW domain-containing oxidoreductase (WWOX) gene cause distinct conditions, including WWOX-related epileptic encephalopathy (WOREE).
Purpose of the Study:
- To establish an in vitro model for DEEs using brain organoids derived from engineered cells and patient-derived cells.
- To investigate the cellular and molecular mechanisms underlying WOREE syndrome.
- To explore potential therapeutic strategies for WOREE.
Main Methods:
- Generation of brain organoids from CRISPR-engineered human embryonic stem cells (ES cells) and patient-derived induced pluripotent stem cells (iPSCs).
- Analysis of cellular and molecular abnormalities within the brain organoid models.
- Assessment of the potential therapeutic effect of ectopic WWOX expression.
Main Results:
- Identified significant CNS abnormalities in the brain organoids, including altered neural populations and cortical differentiation defects.
- Revealed impairment in the Wnt pathway and DNA damage response pathways.
- Demonstrated that restoring WWOX expression could potentially ameliorate observed phenotypes.
Conclusions:
- Brain organoid models are effective for studying childhood epileptic encephalopathies like WOREE.
- These models provide a platform for identifying therapeutic targets and testing interventions for DEEs.
- WWOX dysfunction plays a critical role in the pathogenesis of WOREE.
