Table 1.

Brain disorder modeling with brain region-specific organoids.

Brain organoid subtypes		Psychiatric disorders	Genetic background	Findings	Ref
Forebrain organoids	Cortical organoids	Angelman syndrome	Engineered UBE3A KO hESCs and isogenic controls	Hyperactivity of neurons and networks, which can be rescued by paxilline	(29)
	Cortical organoids	Frontotempor al dementia	Patient iPSCs with tau-V337M and isogenic corrected iPSCs	Affected synaptic maturation and excitatory neuron survivability, which can be rescued by the PIKFYVE kinase inhibitor apilimod	(31)
	Cortical organoids	Autism spectrum disorder	Multiple patient iPSCs	Accelerated cell cycle and overproduction of inhibitory neurons	(16)
	Cortical organoids	Autism spectrum disorder	Engineered heterozygous mutation in SUV420H1, ARID1B or CHD8 with multiple parental iPSCs	Convergent phenotypes with asynchronous development of inhibitory and excitatory neurons	(25)
	Cortical organoids	Autism spectrum disorder	Patient iPSCs with a CNTNAP2 mutation and isogenic corrected iPSCs	Increased neural progenitor proliferation and organoid volume	(26)
	Cortical organoids	Schizophrenia	patient iPSCs with a DISC1 mutation	Disruption of cell cycle with delayed mitosis	(27)
	Cortical organoids	Schizophrenia	patient iPSCs with a DISC1 mutation	Deficits in cortical neuron fate specification	(19)
	Cortical organoids	Fragile X syndrome	Patient iPSCs and isogenic corrected iPSCs	Dysregulated neurogenesis, neuronal maturation and neuronal excitability	(28)
	Cortical organoids	Alzheimer’s Disease	Multiple patient iPSCs	Modeled amyloid aggregation and hyperphosphorylated tau protein, which is rescued by treatment with β- and γ-secretase inhibitors	(30)
	Cortical organoids	Lissencephaly / Miller-Dieker syndrome	Patient iPSCs with heterozygous deletion of chromosome 17p13.3 and rescue cell lines expressing LIS1 or YWHAE	Reduced organoid size caused by premature neurogenesis and can be rescued by Wnt activation	(24)
	Cortical organoids	Lissencephaly / Miller-Dieker syndrome	Patient iPSCs with heterozygous deletion of chromosome 17p13.3 and cell-autonomous corrected line	Reduced organoid size, increased apoptosis and horizontal divisions, and defects in neuronal migration and mitotic spindles	(23)
	Cortical organoids	22q11.2 deletion syndrome	Patient iPSCs	Abnormal neuronal excitability-related gene expression, neuronal excitability and calcium signaling	(76)
	Cortical organoids	Microcephaly	Multiple engineered iPSCs with a WdR62 mutation	Reduction in organoid size due to decreased proliferation and premature differentiation of neural progenitor cells	(20)
	Cortical organoids	Microcephaly	Patient iPSCs with a ASPM mutation	Reduction in organoid size; neurogenesis defects; defective neuronal activity	(21)
	Cortical organoids	Microcephaly	Patient iPSCs from multiple families with missense or frameshift mutations in NARS1	Disruption of protein synthesis; reduction in organoid size due to reduced RGC proliferation	(22)
	Cortical organoids	Microcephaly	Engineered iPSCs with a homozygous mutation in IER3IP1	Reduced organoid size and rosette size which can be restored using ISRIB; increased unfolded protein response and ER stress; decreased extracellular matrix protein	(101)
	Cortical ventral forebrain organoids	Tuberous sclerosis complex	Patient iPSCs with mutations in TSC2 and isogenic corrected iPSC	Brain tumors and cortical malformations caused by over-proliferation of caudal late interneuron progenitor	(125)
	Cortical organoids	Rett syndrome	Patient iPSCs with mutations in MECP2 and isogenic corrected iPSCs	Cell migration deficits in distances, speeds, and radial trajectories	(84)
	Retinal organoids	Retinitis pigmentosa	Patient iPSCs with frameshift mutations in RPGR and isogenic corrected iPSCs	Photoreceptor defects in morphology, localization, transcriptional profiling, and electrophysiological activity	(126)
	ARC organoids	Prader-Willi syndrome	Patient iPSCs with major or minor deletion on the chromosome 15q11-q13	Differentiation and functional deficits	(44)
Midbrain organoids	Midbrain organoids	Parkinson’s disease	Gene edited iPSCs with LRRK2-G2019S mutation	Accumulation of a-synuclein; mimicked the gene expression profiles in patients	(48)
	Midbrain organoids	Parkinson’s disease	Patient iPSCs with LRRK2-G2019S mutation	Decreased number and complexity in the expression of mDANs	(49)
	Midbrain rganoids	Parkinson’s disease	Patient iPSCs with SNCA triplication and CRISPR/Cas9 corrected isogenic control iPSCs	Elevated accumulation of a-synuclein and reduction in dopaminergic neurons	(50)
	Midbrain organoids	Parkinson’s disease	Patient iPSCs with a PINK1 mutation and CRISPR/Cas9 corrected isogenic control iPSCs	Imbalanced proliferation, apoptosis and mitophagy; reduced dopaminergic differentiation, which can be rescued by treatment with HP-β-CD	(52)
Assembloids	Cortical organoids + Microglia assembloids	Alzheimer’s Disease	APP duplicated patient organoids cocultured with APOE3- or APOE4-carrying microglia-like cells	Increased Aβ aggregates and hyperphosphorylation of tau in organoids cocultured with APOE4-microglia	(127)
	Cortical organoids + Blood vessels assembloids	Alzheimer’s Disease	A mixture of control and inducible ETV2-expressing hESCs	Aβ1–42-oligo treatment led to disruption of tight junctions	(62)
	Cortical-ventral forebrain assembloids	Timothy syndrome	Patient iPSCs with a CACNA1C mutation	Abnormal interneuron migration saltation. L-type calcium channel blocker rescued saltatory length	(39)
	Cortical-ventral forebrain assembloids	Timothy syndrome	Patient iPSCs with a CACNA1C mutation	Abnormal interneuron migration saltation. GABA-A receptor antagonism rescued saltatory frequency	(83)
	Cortical-striatal assembloids	Phelan-McDermid syndrome	Patient iPSCs with chromosome 22q13.3 deletion	Cortico-striatal connectivity defects with abnormal calcium activity	(42)
	Cerebral-ganglionic eminence assembloids	Rett syndrome	Patient iPSCs with mutations in MECP2	Transcriptomic differences; epileptiform-like neural network activity that can be rescued by treatment with pifithrin-α	(90)
	Cortical ventral forebrain organoids and assembloids	Rett Syndrome	Patient iPSCs with mutations in MECP2	Premature development of the deep-cortical layer; neural function defects; impaired interneuron migration	(86)