357 General Discussion - hiPSC-CMs Disease Modelling and Future Perspectives 13 hiPSC-CMs for drug screenings, cardiotoxicity, and disease modeling After the initial identification of the molecular mechanism by multi-omics and the subsequent experiments for the gene/protein expression and localization, the complex discoveries need to be studied in the automated screening of many individuals, and in well-controlled hiPSCCM models. These hiPSC lines could not only serve as a proxy for a clinical trial but also have no limitation in the number of different “people” that could be used for screenings. In statistical sample size estimation studies, a sample size of four different cell lines could show the drug toxicity/sensitivity probability of the observations in 34%52, whereas 22 individual lines, roughly the number of individuals in the phase I clinical trial, would achieve a 90% probability of predicting events that occur in 10% of the population. With 250 lines, the assay could predict events in 1% of the population with a 90% probability.53 Moreover, a new successful drug can take more than 10 years to form and be approved, with costs of approximately 2 billion for the whole process. This disappointing reality of promising preclinical findings failing in 89% of the studies from animal models into effective therapies has raised serious concerns within the scientific community.54 The recent FDA Modernization Act 2.0 has opted a way for alternative methods such as hiPSC to bolster the preclinical data pipeline, aiming to reduce the dependence on animal models.55 The combination of bioengineered 3D techniques with hiPSC currently represents our best hope for improving our preclinical-to-clinical trial pipeline for new therapeutics. The costs of these hiPSC-derived microtissues are very low, resulting in the cost for a screening of 22 lines with 5 drug concentrations and 5 replicates per condition to be under 200 euros (±0.22 per spheroid37). This enables big pharma to reduce drug development costs by enabling drug screenings that have a high probability of failing in clinical trials while continuing the development of drugs that are safe for human administration. These phase II-like CTiDs could follow the same principles as the ones of a clinical trial, with similar donor cohort design, scale, and confidence in the prediction. In Chapter 10, we demonstrated that 8 hiPSC lines could be efficiently generated from 6 individuals carrying the PLN-R14del mutation and 2 healthy family members. Moreover, the massive expansion and biobanking described in Chapter 4, and the generation of 3D microtissues in a 96-well (Chapter 11) and 384-well format (Chapter 12) offer great potential for high-throughput (HT) disease modeling and subsequent screening of therapeutic interventions.56 After the efficient development of hiPSC-CM models from any cardiomyopathy and any patient, now more than ever, hiPSC-CMs can be used as “clinical trials in a dish” (CTiD). Unfortunately, not many studies have used 4 or more individuals’ hiPSC-CMs for the prediction of drug response, cardiac toxicity, or disease modeling (Table 1). In practice, the validation of hiPSC-CM-based cardiotoxicity as studies described a good correlation between in vitro cardiotoxicity and the clinical incidence of cardiotoxicity. Contrary to expectations, however, a recent study investigating the overlap between the drug response to dofetilide and moxifloxacin in 16 hiPSC lines of both subjects and the corresponding subject-derived hiPSC-CMs, failed to find a significant correlation.62 Therefore, to study
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