Table 1.

Selected studies investigating neurological disorders/deficits using human brain organoids.

Disease	Studies	Organoid type	Methods of generation	outcomes
Primary microcephaly	Lancaster et al., 2013 [14]	Cerebral organoids	Patient iPSC-derived; CDK5RAP2 mutation	Fewer progenitor cells, premature neuronal differentiation; CDK5RAP2 overexpression rescued the mutant phenotypes
	Li et al., 2017 [70]	Cerebral organoids	Patient iPSC-derived; ASPM mutation	Reduced organoid size, fewer progenitor cells in VZ and oSVZ, poor lamination, reduced neuronal calcium activity
	Gabriel et al., 2016 [75]	Cerebral organoids	Seckel patient iPSC-derived; CPAP mutation	Delayed cilia disassembly led to premature differentiation of NPCs and reduced progenitor pools
	Zhang et al., 2019 [134]	Cerebral organoids	hPSC-derived; CRISPR/Cas9-mediated homozygous knockout of WDR62	Delayed cilia disassembly and retarded cell cycle progression led to reduced proliferation and premature differentiation of NPCs
Autism spectrum disorder (ASD)	Mariani et al., 2015 [15]	Cortical organoids	Idiopathic ASD patient iPSC-derived	Altered transcriptomic profiles, particularly FOXG1 upregulation; accelerated cell cycles; increased GABAergic neuron production, can be rescued by RNAi-mediated FOXG1 knockdown
	Wang et al., 2017 [76]	Cerebral organoids	hiPSC-derived, CRISPR/Cas9-mediated heterozygous mutation of CHD8 (CHD8+/-)	Upregulation of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/β-catenin signaling, and axonal guidance
Tuberous sclerosis complex (TSC)	Blair et al., 2018 [81]	Cortical spheroids	CRISPR/Cas9-mediated homozygous knockout of TSC1 or TSC2 in hESCs	mTORC1 hyperactivation, reduced neurogenesis, increased gliogenesis; dysplastic cells in TSC2−/− cortical spheroids can be rescued by early and continuous rapamycin treatments
Neonatal hypoxia-ischemia injury	Boisvert et al., 2019 [82]	Cerebral organoids	hESC-derived; 72-hour under hypoxic environment	Inhibition of dorsal-related genes such as FOXG1, CTIP2, and TBR1; could be alleviated by minocycline
	Pasca et al., 2019 [84]	Cortical spheroids	hiPSC-derived; 48-hour under hypoxic environment	Reduction of TBR2+ intermediate progenitors led to cell cycle damage and premature neural differentiation; rescued by ISRIB treatments
ZIKV-associated microcephaly	Qian et al., 2016 [17]	Cortical organoids	hiPSC-derived; MR766 and FSS13025 ZIKV strain infected	Reduced organoid size, reduced neuronal layer thickness, expanded ventricular lumen, increased cell death
	Dang et al., 2016 [87]	Cerebral organoids	hESC-derived; MR766 ZIKV strain infected	Reduced organoid size, TLR3 upregulation and TLR3-mediated transcriptomic alterations; direct inhibition of TLR3 reduced phenotypes
	Watanabe et al., 2017 [88]	Cortical organoids	hPSC-derived; PRVABC59 ZIKV strain infected	Activated innate immune responses led to increased progenitor apoptosis and reduced organoid size; duramycin or ivermectin rescued the teratogenic effects of ZIKV infection
SARS-CoV-2-associated neurological deficits	Jacob et al., 2020a [98]	Cortical, hippocampal, hypothalamic, midbrain, and ChP organoids	hiPSC-derived; SARS-CoV-2 USA-WA1/2020 infected	Particular tropism for ChP epithelial cells, caused increased cell death, transcriptional dysregulation, disrupted ChP epithelial integrity and barrier function
	Pellegrini et al., 2020 [100]	Cerebral and ChP organoids	hPSC-derived; SARS-CoV-2 spike pseudovirus and live virus infected	Particular tropism for ChP epithelial cells of cerebral organoids; infected cells expressing ACE2 and lipoproteins; ChP epithelial integrity and barrier function were disrupted
Alzheimer's disease (AD)	Gonzalez et al., 2018 [102]	Cerebral organoids	Familial AD or DS patient iPSC-derived	β-Amyloid (Aβ) aggregation, formation of neurofibrillary tangle-like structures, hyperphosphorylated tau, increased cell apoptosis
	Lin et al., 2018 [109]	cerebral organoids	CRISPR/Cas9-generated isogenic iPSC lines homozygous for APOE4 alleles	Increased Aβ accumulation and tau phosphorylation
Parkinson's disease (PD)	Kim et al., 2019a [34]	Midbrain organoids	CRISPR/Cas9-generated isogenic iPSC lines harboring LRRK2 G2019S mutation	Shortened neurite length and decreased marker expression of mDAN; increased aggregation and abnormal clearance of α-synuclein; inhibition of upregulated TXNIP ameliorated mutant phenotypes
	Wulansari et al., 2021 [114]	Midbrain organoids	CRISPR/Cas9-mediated homozygous knockout of DNAJC6 in hESCs	mDAN degeneration, α-synuclein aggregation, increased neuronal firing frequencies, mitochondrial and lysosomal defects
Huntington's disease (HD)	Conforti et al., 2018 [133]	Cerebral organoids	Patient iPSC-derived	Defective progenitor identity acquisition, abnormal neuronal specification, and disrupted cellular organization
	Zhang et al., 2019 [134]	Cerebral organoids	Patient iPSC-derived and isogenic HD hESC-derived	Impaired cell cycle, disrupted neuroepithelial structures, and premature neurogenesis
Glioblastoma	Linkous et al., 2019 [139]	Cerebral organoid glioma (GLICO)	Patient-derived glioma stem cells cocultured with hESC-derived cerebral organoids	Rapid and deep invasion of glioblastoma cells into cerebral organoids; invasive tumor phenotypes in hybrid organoids
	Jacob et al., 2020b [143]	Glioblastoma organoids	Patient-derived	Recapitulated histological, cellular, and transcriptomic features of glioblastoma; aggressive infiltration after transplantation

hPSC: human pluripotent stem cell, including hiPSC and hESC; hiPSC: human-induced pluripotent stem cell; hESC: human embryonic stem cell; VZ: ventricular zone; oSVZ: outer subventricular zone; NPC: neural progenitor cells; ChP: choroid plexus; DS: Down syndrome; mDAN: midbrain dopaminergic neuron.