Human iPSC modeling of heart disease for drug development

Abstract

Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human cells that reproduce hallmark features of heart disease in the culture dish. Their potential applications include the discovery of mechanism-specific therapeutics, the evaluation of safety and efficacy in a human context before a drug candidate reaches patients, and the stratification of patients for clinical trials. Although this new technology has the potential to revolutionize drug discovery, translational hurdles have hindered its widespread adoption for pharmaceutical development. Here we discuss recent progress in overcoming these hurdles that should facilitate the use of hiPSCs to develop new medicines and individualize therapies for heart disease.

Keywords: HTS; cardiomyocyte; disease modeling; drug attrition; drug discovery; heart disease; hiPSC; screen.

Figure 1. Value added benefit of hiPSC-CMs for drug development

The potential benefit of hiPSC-CMs for drug development includes disease models that bring the human context to discovery and preclinical stages. hIPSC-CM based studies could also be used to discriminate drug-responsive patients with a specific disease that would allow a more precise Phase II clinical trial to be performed. Together, these technologies might improve the efficiency of drug development. In addition, hiPSC-based phenotyping, combined with multi-omics analyses of patient samples, would aid clinicians in prescribing medicines on the basis of mechanism and drug-responsiveness.

Figure 2. Comparison Between Arrayed and Pooled Functional Genomics Screens.

A) hiPSC-CMs expressing Cas9 can be plated into microtiter plates and wells transfected with individual CRISPR guide RNAs, siRNAs, or miRNAs. Each well can then be assayed for cardiomyocyte function, such as calcium handling or contractility, or marker expression to call “hits”. B) In pooled CRISPR-based screening, hiPSC-CMs are transduced with a lentiviral library of CRISPR guides. A selection is applied to enrich or deplete a phenotype of interest. The populations are then pooled, DNA is extracted, and guides are counted using Next Generation Sequencing. Enriched guides are called as “hits”. C) The two approaches can be combined in series. This allows for the identification of functionally relevant “hits”.

Figure 3. In Vitro hiPSC-CM Testing for Predicting Drug Safety and Efficacy in Humans.

A) hiPSC-CMs from healthy donors can be used in a clinical trial in a dish (CTiD) to assess susceptibility to drug-induced toxicity. Cardiac toxicity is the most frequent adverse drug reaction. B) hiPSC-CMs carrying predisposing genetic risk factors can be used to predict the effect in human carriers. The incidence of such effects might be undetected in clinical trials due to the rarity of the predisposing genetic variants. C) hiPSC-CM models of the target patient population can be used to predict the therapeutic effects of an investigational molecule. In the case of a genetic model, genome-corrected isogenic hiPSC-CMs are important controls for genetic background and hiPSC interline variation.