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 stem cells (iPSCs). We observed mature astrocytes, oligodendrocytes, and myelin within 8 weeks, greatly shortening the culture period. Compared with the wild type, mutant organoids displayed a smaller size and contained increased immature and dysfunctional astrocytes, oligodendrocytes, and sparse myelin. Abnormal overactivation of the UPR pathway was also present in mutant cerebral organoids. Additionally, we found that the maturation and function of these cells in mutant organoids were significantly improved after ISRIB treatment, which also inhibited hyperactivation of the unfolded protein response (UPR) signaling pathway. CONCLUSIONS: Our study established a rapid myelinating oligodendrocyte brain model in VWM for the first time, providing a more effective and tractable platform for further study of this condition and other white matter diseases. Furthermore, our findings suggested that ISRIB may have potential as a clinical treatment for VWM.