Table 1 Summary of representative studies using hPSC-derived cardiomyocytes to enhance cardiac drug development.
From: Intensive care for human hearts in pluripotent stem cell models
Objective | Design | Readouts | Comments | Refs. |
|---|---|---|---|---|
Safety pharmacology | Hoffman-La Roche: 28 compounds | MEAs, impedance | Improved accuracy over hERG screening | |
Safety pharmacology | GSK: 10 compounds | MEAs | Concurred with rabbit ventricular wedge | |
Safety pharmacology | J&J: 20 compounds | MEAs | 90% accuracy for known toxicities | |
Safety pharmacology | Quintiles: 24 compounds | Impedance, cell number, cTnI, ROS, lipid acumulation | ||
Safety pharmacology | AZ: 51 compounds | Intracellular Ca2+, edge detection | 87% sensitivity, 70% specificity | |
Safety pharmacology | CiPA: 28 compound screen, 10-site study | MEAs, voltage-sensitive dye | Blinded, AUC 0.87 | |
Safety pharmacology | JiCSA: 60 compounds | MEAs | Marker of risk for onset of Torsade de pointes | |
Safety pharmacology | CRACK IT InPulse | Contractility, metabolic maturation | Substrate microarrays, EHT | |
Safety pharmacology | HER2-targeted liposomal DOX | DOX uptake, viability, apoptosis | Phase 2: no efficacy against breast cancer | |
Long QT syndrome | Protein chaperone to fix hERG trafficking | MEAs | Successfully advanced to first-in-human study | |
Coxsackie B myocarditis | 4 known anti-virals | CVB3-luc | CAR expression 30× lower than in adult LV | |
Cardiac hypertrophy | ET-1-induced hypertrophy | BNP (hypertrophy), nuclear count (toxicity) | 384-well format | |
Diabetic cardiomyopathy | Phenotype-driven screen | BNP, sarcomere integrity, Ca2+ transients, impedance, electrophysiology | Protective compounds identified | |
Cardiotoxicity | Protocols to derive & analyze hPSC-CMs | Imaging viability and contractility | Development of “cardiac safety index” | |
Cardiotoxicity | TKI-induced toxicity: 21 compounds | Viability, contractility, Ca2+ transients; RTK phosphorylation | Protection by IGF1 or insulin | |
Cardiotoxicity | DOX-induced toxicity; TOP2B disruption by CRISPR-Cas9 | Viability, ΔΨm, ROS, [Ca2+]i, DNA damage, MEAs, RNA-seq | Role of TOP2B substantiated | |
Cardiotoxicity | TKI-induced and DOX-induced toxicity | RNA-seq, mass spec, mitochondrial function, metabolomics | TKIs disrupt metabolism; DOX induces DNA damage | |
Cardiomyocyte survival | Genetic & small molecule inhibitors of MAP4K4 | Viability, apoptosis, Ca2+ cycling, mitochondrial function, force generation | Protection in 2D & 3D culture; reduced infarct size in mice | |
Cardiomyocyte survival | Phenotype-driven HTS | Viability, expression of cardioprotective genes | HO-1 correlates with myocyte protection | |
Cardiomyocyte proliferation | Phenotype-driven HTS | High-throughput proteomics, RNA-seq | Pro-proliferative compounds identified |
