Open AccessModeling genetic epileptic encephalopathies using brain organoids
Author(s) -
Steinberg Daniel J,
Repudi Srinivasarao,
Saleem Afifa,
Kustanovich Irina,
Viukov Sergey,
Abudiab Baraa,
Banne Ehud,
Mahajnah Muhammad,
Hanna Jacob H,
Stern Shani,
Carlen Peter L,
Aqeilan Rami I
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013610
Subject(s) - wwox , biology , population , neuroscience , organoid , phenotype , epilepsy , medicine , genetics , cancer , suppressor , gene , environmental health
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.