Table 1.

Human disease conditions modeled using brain organoids.

Disease/condition	Cells/genetic background	Phenotypes in organoids	References
Microcephaly-related phenotypes
Primary microcephaly	Microcephaly patient-derived hiPSCs carrying mutations in CDK5RAP2 gene.	Smaller organoids. Premature neurogenesis and exhaustion of neural stem cells.	[14]
	Microcephaly patient-derived hiPSCs carrying mutations in ASPM gene.	Smaller organoids.	[123]
	iPSCs genetically edited to delete WDR2 gene.	Smaller organoids. Premature neurogenesis and reduction in ventricular and outer radial glia.	[103]
Seckel syndrome	Seckel syndrome patient-derived hiPSCs carrying mutations in CPAP gene.	Smaller organoids with perturbed neural rosette morphology. Perturbed cilium disassembly, delayed cell cycle reentry and premature neuronal differentiation.	[124]
Zika virus infection-induced microcephaly	Organoid infection with human Zika virus.	Infection of neural progenitors in the organoids affected their proliferative capacity, led to premature neurogenesis and increased cell death leading to reduced organoid size. Chemical screen of infected organoids for their ability to neutralize Zika virus and ameliorate the neurological defects.	[15, 105–109]
Aicardi–Goutières syndrome (AGS)	Gene-edited hESCs and AGS patient-derived hiPSCs carrying mutations in TREX1 gene.	Smaller organoids with reduced proliferation and higher neurotoxicity. Similar neurotoxicity in control organoids treated with TREX1 mutant astrocyte-conditioned medium (due to action of secreted interferons).	[125]
Macrocephaly-related phenotypes
Macrocephaly	hPSCs gene-edited for PTEN loss of function.	Enhanced AKT signaling, transiently delayed neuronal differentiation, and expanded ventricular progenitors and intermediate progenitor pools. Appearance of folds on the organoid surface.	[113]
Sandhoff disease	Sandhoff disease patient-derived hiPSCs carrying mutations in HEXB gene.	Accumulation of GM2 ganglioside, increased organoid size and higher progenitor proliferation.	[126]
Lissencephaly Miller–Dieker syndrome (MDS)	MDS patient-derived hiPSCs with heterozygous deletions of human region 17p13.3.	Smaller organoids with perturbed neural rosette morphology and perturbed plain of division. Neuronal migration defects and increased number of deep layer neurons at late stages.	[127, 128]
Periventricular heterotopia	Periventricular heterotopia patient-derived hiPSCs carrying mutations in DCSH1 and FAT4 genes	Defect in the morphology of radial glia cells, altered neuronal state in a subset of neurons resulting in defective migration and heterotopic localization of neurons.	[55]
Glioblastoma	Oncogene activation in brain organoids.	Neoplastic tissue development in the organoid. Transplantation of the organoid tumor in the mouse further formed a clinical tumor. Organoids used as platform to screen anti-cancer drugs.	[129, 130]
	Coculture of patient-derived glioma stem cells with cerebral organoids.	Neoplastic tissue development in the organoid. Organoids used as platform to screen anti-cancer drugs.	[92, 93]
Autism spectrum disorder (ASD) related
ASD	Organoids grown from ASD proband-derived hiPSCs.	Faster cell cycle of progenitors leading to overproduction of neurons. Misregulated expression of FOXG1 linked with higher production of GABAergic interneurons over glutamatergic excitatory neurons.	[48]
ASD with macrocephaly	Organoids grown from ASD proband-derived hiPSCs.	Perturbed morphology of deep layer neurons	[131]
Rett syndrome	Rett syndrome proband-derived hiPSCs.	Neural rosette phenotype with deregulated neurogenesis and miRNA expression.	[132]
Neurodegenerative disorders
Parkinson’s disease (PD)	PD patient-derived hiPSCs carrying LRRK2-G2019S mutations.	Reduced generation and complexity of midbrain dopaminergic neurons.	[76, 77]
Alzheimer’s disease (AD)	AD patient-derived hiPSCs carrying familial AD mutations in AD precursor protein or PSEN1.	Occurrence of amyloid β (Aβ) aggregates, hyperphosphorylated tau and structures similar to amyloid plaques and neurofibrillary tangles. Electrophysiological recordings revealed increased excitatory bursting activity. Coculture of AD organoids with microglia reduces Aβ aggregates.	[87, 118, 133, 134]
Fronto-temporal dementia (FTD)	FTD patient-derived hiPSCs carrying the TAU P301L mutation.	TAU phosphorylation. Overexpression of modified form of p35 reduced levels of phosphorylated TAU and increased expression of synaptophysin.	[135]
Psychiatric disorders
DISC1 mutation	hPSCs gene-edited to delete DISC1 gene.	Perturbed morphology of the neural rosettes	[136]
	Schizophrenia patient-derived hiPSCs carrying DISC1 mutation.	Perturbed progenitor proliferation and delayed cell cycle in organoids carrying DISC1 mutation or overexpressing truncated DISC1.	[137]
Epilepsy-related disorders
Tuberous sclerosis	iPSCs gene-edited for TSC1 and TSC2 genes.	Reduced neurogenesis and increased gliogenesis. Higher mTOR signaling and dysmorphic cells in the organoids. Defects reduced with rapamycin treatment.	[138]
Timothy syndrome	iPSCs carrying the L-type calcium channel mutation	DV fusion of ventral telencephalic organoids grown from Timothy syndrome patient-derived hiPSCs with control dorsal telencephalic organoids: the interneurons carrying the channel mutation showed cell autonomous defects in saltatory migration. Applying chemical agent that reduced the activity of the L-Type calcium channel lowered the impact of the mutation and rescued the migratory defects.	[19]
Angelman syndrome (AngS)	hPSCs gene-edited to delete UBE3A gene. hiPSCs from AngS patient carrying microdeletion of region including UBE3A gene.	Cortical organoids grown from UBE3A-deficient hPSCs showed increased levels of voltage dependent big potassium channels (BK). Compared with control neurons, neurons from the UBE3A-deficient organoids exhibited enhanced excitability and frequent firing. Effects rescued by BK antagonist treatment.	[119]
Hypoxia		Organoid culture at different oxygen concentrations induced unfolded protein response that could be reduced with integrated stress response inhibitor (ISRIB) treatment or microcephalic phenotype that could be reduced by Minocycline treatment	[139, 140]
Downs Syndrome (DS)	DS patient-derived hiPSCs with trisomy 21.	Misregulated expression of OLIG2 leading to overproduction of GABAergic interneurons.	[46]