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Table 2 Modeling neurological disorders with 3D brain organoids derived from human pluripotent stem cells

From: 3D brain Organoids derived from pluripotent stem cells: promising experimental models for brain development and neurodegenerative disorders

Disease Gene/Substance Type of PSCs Brain region Disease phenotype in organoid Disease mechanism Therapeutic strategies Reference
Microcephaly CDK5RAP2 Human iPSCs Cerebral cortex Smaller neuroepithelial regions, altered spindle orientation of radial glial cells, abundant neuronal outgrowth, smaller organoid size Heterozygous nonsense mutation in CDK5RAP2 Reintroducing CDK5RAP2 protein [34]
Impaired brain growth ZIKV Human iPSCs Forebrain Increased cell death and suppressed proliferation of neural progenitors, decreased neuronal layer thickness and organoid size, enlarged lumen/ventricles - - [36]
Impaired brain growth ZIKV Human ESCs Cerebral cortex Attenuated brain organoid growth TLR3-mediated dysregulation of neurogenesis TLR3 inhibitor [57]
Impaired brain growth ZIKV Human iPSCs Cerebral cortex Reduced viability and growth of neural progenitor cells, smaller brain organoid size - - [58]
Impaired brain growth ZIKV Human ESCs/iPSCs Cerebral cortex Increased apoptosis in neural progenitors, reduction of prolifration zone, disrupted cortical layers - - [59]
Impaired brain growth Cocaine Human ESCs Neocortex Proliferation inhibition of neuroepithelial progenitors, premature neuronal differentiation, reduction in cortical plate formation CYP3A5-mediated cocaine oxidative metabolism CYP3A5 inhibitor/Knockdown of CYP3A5 [40]
Autism spectrum disorder/macrocephalic phenotype - Human iPSCs Dorsal telencephalon Increased progenitor cell proliferation, enhanced synaptic maturation, overproduction of GABAergic inhibitory neurons Overexpression of transcription factor FOXG1 Knockdown of FOXG1 [86]
Early-onset familial Alzheimer’s APP Human iPSCs Neocortex β-amyloid (Aβ) aggregation, hyperphosphorylated Tau (pTau), endosome abnormalities APP duplication β- and γ-secretase inhibitors [93]