Effects of the Small‐Molecule ISRIB on the Rapid and Efficient Myelination of Oligodendrocytes in Human Stem Cell‐Derived Cerebral Organoids in Patients With Leukoencephalopathy With Vanishing White Matter

作者：Wei Yan, Jiong Deng, Jie Zhang, Kai Gao, Huan Yi, Junjiao Zhang, Fan Zhang, Jingmin Wang, Yuwu Jiang, Ye Wu · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1111/cns.70398 · 被引用次数：4 · 研究领域：RNA regulation and disease、Endoplasmic Reticulum Stress and Disease、Neurogenesis and neuroplasticity mechanisms

INTRODUCTION: Leukoencephalopathy with vanishing white matter (VWM) is a rare genetic disorder caused by mutations in any one of the EIF2B1-5, which encode subunits of eukaryotic translation initiation factor 2B (eIF2B). Previous studies suggested that the dysfunction of astrocytes played a central role in the pathogenic mechanism of VWM. In addition, eIF2B participates in the unfolded protein response(UPR) by coordinating the integrated stress response (ISR). Higher susceptibility to endoplasmic reticulum stress (ERS) and abnormal overactivation of the unfolded protein response (UPR) were found in VWM, which led to logical deterioration and exacerbation of cell death. There are currently no specific treatments available for VWM. AIM: Previous studies have successfully constructed three-dimensional brain organoids that can be used to study the development of neuronal cells during brain development. In this study, we aimed to develop a more rapid and efficient brain organoid model that would produce mature astrocytes, oligodendrocytes, and myelin within 8 weeks. The small-molecule ISR inhibitor (ISRIB) is a specific eIF2B activator by inhibiting the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Thus, ISRIB is used on eIF2B mutant organoids to determine its potential as a therapeutic approach for VWM. RESULTS: We constructed EIF2B4 and EIF2B5 mutants as well as wild-type rapid myelinating oligodendrocyte brain organoids using human induced pluripotent st...