Journal Article

Modeling genetic epileptic encephalopathies using brain organoids

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

2021

Overview

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. SYNOPSIS Mutations in the human WWOX gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions. At early stages of development WWOX is highly expressed in neural stem cells called ventricular radial glia (vRGs). WWOX ‐mutated brain organoids have imbalanced levels of excitatory and inhibitory neurons and are hyperexcitable, demonstrating epileptiform activity upon electrophysiological recordings. WWOX mutations cause increased astrogenesis and cortical dysplasia. WOREE‐modeled organoids have impaired DNA damage response and chronic activation of the Wnt‐signaling pathway. WWOX gene reintroduction could benefit patients suffering from WWOX mutations. Graphical Abstract Mutations in the human WWOX gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Analysis / Ataxia / Brain / cerebral organoids / Children / Cloning / Convulsions & seizures / CRISPR / DNA damage / EMBO16 / EMBO27 / Encephalopathy / Epilepsy / Microcephaly / Mutation / Organoids / Oxidoreductase / Pathogenesis / Patients / Phenotypes / Physiology / Population changes / SCAR12 / Seizures / Seizures (Medicine) / Stem cells / Tumor suppressor genes / Wnt pathway / Wnt protein / WOREE syndrome