Table 2.

High-Throughput Drug Discovery and Development Assays Using iPSC-based Systems.

Disease/Purpose	Assay Description	Results	Reference
α-1 Antitrypsin Deficiency	Screened over 3000 compounds from the Johns Hopkins Drug library using immunofluorescence to determine effect on AAT levels	Five hits confirmed to cause consistent reduction in AAT across multiple iPSC lines	[103]
Liver Fibrosis	Screened over 1400 compounds using a red fluorescent protein reporter line to assay inhibition of stellate cell activation	Two compounds suitable for oral administration identified as potential treatments for liver fibrosis	[97]
Familial Hypercholesterolemia	Screened over 2300 small molecules from the SPECTRUM collection drug library using an ELISA-based assay to detect ApoB secretion	Identified cardiac glycosides as potential treatment for lowering ApoB secretion	[13]
mtDNA Depletion Syndrome	Screened over 2300 small molecules from the SPECTRUM collection drug library using a luciferase ATP assay to identify drugs that could restore ATP levels	Identified NAD as being able to improve ATP production and mitochondrial function	[56]
Niemann–Pick Disease Type C	Used a series of 2-hydroxypropyl-cyclodextrins to determine impact on cholesterol accumulation and hepatic function	Identified HPGCD as potential treatment for NPC	[87]
Non-alcoholic Fatty Liver Disease	Screened 13,000 compounds from AstraZeneca chemogenic library using BODIPY staining to quantify intracellular neutral lipid droplets	21 confirmed hits identified CDK2-4-C/EBPα/DGAT2 pathway as therapeutic target for lowering lipid accumulation	[95]
Identifying regulatory pathways for hepatic differentiation	Screened over 1100 small molecules using immunofluorescence to quantify HNF4α levels	Identification of HSP90β as a regulator of hepatic progenitor formation	[96]
Toxicity Screening	Generated mCherry-tagged CYP1A1 HLCs and screened 241 chemicals to identify aryl hydrocarbon receptor modulators	Five novel hits determined to up- or down-regulate expression of CYP1A1 in HLCs	[98]
	Developed a 3D coculture model with macrophages and endothelial cells; screened 159 known toxic compounds for effects on hepatic function	Identified albumin expression assay as most-sensitive method for calculating TC50 values with this system	[99]
	Screened 238 marketed drugs using liver organoids in a multiplexed readout assay	Validated high predictive values for effects on viability, cholestatic, and/or mitochondrial toxicity	[100]
	Developed noncontact coculture model of liver spheroids and renal proximal tubule cells to assay liver and kidney toxicity simultaneously	Demonstrated toxicity profiles could be discriminated with known toxic CYP inhibitor compound CsA	[101]
	Screened 47 compounds for effects on albumin, urea, and ATP levels using micropatterned coculture of HLCs and murine embryonic fibroblasts	Micropatterned coculture model showed similar sensitivity for toxic drug identification to primary hepatocyte model	[102]