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Modeling genetic epileptic encephalopathies using brain organoids
EMBO Molecular Medicine ( IF 11.1 ) Pub Date : 2021-07-15 , DOI: 10.15252/emmm.202013610
Daniel J Steinberg 1 , Srinivasarao Repudi 1 , Afifa Saleem 2, 3 , Irina Kustanovich 4 , Sergey Viukov 5 , Baraa Abudiab 1 , Ehud Banne 6, 7 , Muhammad Mahajnah 8, 9 , Jacob H Hanna 5 , Shani Stern 4 , Peter L Carlen 2, 3, 10 , Rami I Aqeilan 1
Affiliation  

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.

中文翻译:

使用脑类器官模拟遗传性癫痫性脑病

发育性和癫痫性脑病 (DEE) 是一组与顽固性癫痫发作、大脑发育和功能异常相关的疾病,在某些情况下还会导致过早死亡。含肿瘤抑制因子 WW 结构域的氧化还原酶 ( WWOX )的致病性人类种系双等位基因突变与相对轻微的常染色体隐性遗传脊髓小脑共济失调 12 (SCAR12) 和更严重的早期婴儿WWOX相关癫痫性脑病 (WOREE) 相关。在这项研究中,我们以破坏性的 WOREE 综合征为原型,通过 CRISPR 工程改造的人类 ES 细胞和患者来源的 iPSC 建立大脑类器官,生成了 DEE 的体外模型。使用这些模型,我们发现了中枢神经系统显着的细胞和分子异常,包括神经群体变化、皮质分化功能障碍以及 Wnt 通路和 DNA 损伤反应损伤。此外,我们提供了一个概念证明,即异位WWOX表达可能会挽救这些表型。我们的研究结果强调了使用脑类器官模拟儿童癫痫性脑病的实用性,以及它们作为测试可能的治疗干预策略的独特平台的用途。
更新日期:2021-08-09
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