Table 2.

Drug screening of patient-specific iPSC derivatives

Disease	Drug	Cell type	Outcome	Ref.
Familial dysautonomia	6912 compounds tested; 8 hits	Neural crest lineage precursors	Alpha-2 adrenergic receptor activity implicated in regulating IKBKAP expression. SKF-86466 induced IKBKAP transcription through regulation of intracellular cAMP levels/PKA-dependent CREB phosphorylation. Restored expression of autonomic neuron markers.	(Lee et al. 2012)
Gaucher’s/Parkinson’s disease	NCGC607, non-inhibitory chaperone of glucocerebrosidase	mDA neurons	Restored glucocerebrosidase activity and reduced α-synuclein levels.	(Aflaki et al. 2016)
Motor neuron disease (TARDBP)	Trichostatin A (a histone deacetyltransferase inhibitor) Spliceostatin A (a spliceosomal factor inhibitor). Anacardic acid and garcinol (histone acetyltransferase inhibitors)	spM neurons	Gene expression analysis suggested transcription and RNA splicing altered in ALS MN. Anacardic acid reduced arsenite-induced death compared with non-treated, reduced TDP-43 mRNA expression and increased length of neurites.	(Egawa et al. 2012)
Motor neuron disease (SOD1)	5000 compounds at 2 concentrations. Kenpaullone identified. Also trialed dexpramipexole—failed phase III clinical trials.	spM neurons	Increased number of surviving spM neurons. 9 compounds identified and particularly kenpaullone, a dual-kinase inhibitor. Kenpaullone promoted survival and supported the morphology and function of the spM neurons in SOD1 mouse model. Subsequently shown to promote survival in MND iPSC-derived spM neurons. Dexpramipexole: no improvement in survival.	(Yang et al. 2013b)
Spinal muscular atrophy	Valporic acid and tobramycin	spM neurons	Treated spM neurons demonstrated 2–3× increased SMA protein compared with untreated.	(Ebert et al. 2009)
	Small-molecule inhibitors of ER stress: 4-phenylbutyrate, kifunensine, salubrinal, guanabenz, and GSK2606414.	spM neurons	Success assessed by spM neuron survival and stress response. Cell culture model accurately predicted in vivo response in SMA mice with guanabenz most successfully.	(Ng et al. 2015)
Alzheimer’s disease	Compound E (γ-secretase inhibitor) Compound W (selective Aβ42 reduction)	Cortical neurons	Dose-dependent reduction in Aβ42 and Aβ40 with compound E. Decrease in ratio of Aβ42 to Aβ40 with compound W.	(Yagi et al. 2011)
		Cortical neurons	Scalable high-throughput model for targeting tau aggregation model.	(Medda et al. 2016)
Fragile X syndrome	4000 Compounds tested	Neural stem cells, validation in neurons	FMRP product of FMR1 gene assay developed. Levels inversely proportional to clinical severity of patient. Identified 6 compounds able to, at least partially, reactivate FMR1 gene in primary screen and then validated in NSCs and neurons at different concentrations. Tibrofan: positive response in neurons.	(Kumari et al. 2015)
	50,000 compounds tested to reactivate Fmr1 gene.	Neuronal precursors	Found several compounds induced weak expression of fragile X mental retardation protein.	(Kaufmann et al. 2015)
Toxicity studies using hiPSC-derived neurons	Tested library of 80 compounds on 384-well plates with a 6-point concentration range.	Neurons β-III tubulin/MAP2 positive	Specifically looked at toxic effect on neurite outgrowth. Identified 6 compounds known to be neurotoxic.	(Ryan et al. 2016)
	2000 compounds	Neuronal precursors	Compared findings with rat cortical neurons to identify selective toxicity. Confirmed findings in second screen using hiPSC-derived neurons and fetal astrocytes with >80% showing cell specific toxicity.	(Malik et al. 2014)