Evaluating human induced pluripotent stem cell-derived cardiomyocytes for commercial drug testing

Katili, Puspita Anggraini (2020) Evaluating human induced pluripotent stem cell-derived cardiomyocytes for commercial drug testing. PhD thesis, University of Nottingham.

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Abstract

The cost of developing new drugs has increased by ~100 fold in recent decades, largely due to high attrition rate in clinical development caused by cardiotoxicity. Since the recent discovery of human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs), it has been developed as a novel, promising in vitro research tool in preclinical testing of drug-induced cardiotoxicity. However, major limitation of currently available hiPSC-CMs is their immature phenotype, which can hinder evaluation of contractile dysfunction.

Existing contractility monitoring on hiPSC-CMs is currently being done at low throughput or by using surrogate markers (e.g. impedance). In addition, there has been no detailed cross-site validation study to evaluate the effect of drugs on hiPSC-CMs contractility. A multinational consortium was established with the University of Nottingham as the academic lead, in order to address the CRACK-IT InPulse Challenge. The Challenge consisted of two phases that lasted for 3.5 years.

This project was part of the consortium aimed to develop medium throughput technology platform that could measure contractility in hiPSC-CMs as a physiologically-relevant functional output for use in preclinical drug safety evaluation. The University of Nottingham utilised CellOPTIQ® platform, a medium-high throughput screening platform to measure contractility and electrophysiology.

Protocols were unified across all academic partners via a drug training set in phase 1, allowing subsequent blinded multi-centre evaluation of drugs with known positive, negative, or neutral inotropic effects in phase 2. Accuracy ranged from 44% to 85% across the platform-cell configurations. Refinement to test conditions was addressed after blinded testing, which resulted in increased accuracy to 85% for 2D monolayers and 93% for 3D EHT system.

Through this study, hiPSC-CMs cultured in 2D and 3D platform have been shown to considerably have a value in predictive safety pharmacology despite their immaturity status and current technology evolution.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Denning, Chris
Thompson, Alexander
Keywords: Drugs, Human induced pluripotent stem cell–derived cardiomyocytes
Subjects: Q Science > QH Natural history. Biology > QH573 Cytology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 60613
Depositing User: Katili, Puspita
Date Deposited: 29 Jul 2020 08:52
Last Modified: 29 Jul 2020 09:00
URI: http://eprints.nottingham.ac.uk/id/eprint/60613

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