Human-induced pluripotent stem cell approaches to model inborn and acquired metabolic heart diseases

Abstract

Purpose of review This article provides an overview of advances in the induced pluripotent stem cell field to model cardiomyopathies of inherited inborn errors of metabolism and acquired metabolic syndromes in vitro. Recent findings Several inborn errors of metabolism have been studied using “disease in a dish” model, including Pompe disease, Danon disease, Fabry disease, and Barth syndrome. Disease phenotypes of complex metabolic syndromes, such as diabetes mellitus and aldehyde dehydrogenase 2 deficiency have also been observed. Summary Differentiation of patient- and disease-specific induced pluripotent stem cell-derived cardiomyocytes has provided the capacity to model deleterious cardiometabolic diseases to understand molecular mechanisms, perform drug screens, and identify novel drug targets.

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

“… First, we hypothesized that a population of iPSCs, rather than a single donor, would improve predictive accuracy. This hypothesis was motivated by studies showing that congenital susceptibilities are recapitulated in iPSC‐derived cardiomyocytes as well as previous studies showing good correlation but poor quantitative accuracy between in vitro and in vivo effective concentrations using a single donor . We found that by averaging over the unique susceptibilities of individual donors, our population‐based predictions were more accurate than those based on any single donor. Second, we posited that the in vitro decay‐rise ratio (time from peak to baseline divided by time from baseline to peak) of calcium flux could be a high throughput, easily measured surrogate for the in vivo QTc interval.…”

“…This hypothesis was motivated by studies showing that congenital susceptibilities are recapitulated in iPSC-derived cardiomyocytes 17,22,23,26,27 as well as previous studies showing good correlation but poor quantitative accuracy between in vitro and in vivo effective concentrations using a single donor. 28 We found that by averaging over the unique susceptibilities of individual donors, our population-based predictions were more accurate than those based on any single donor.…”

“…The ability to generate cells from individual donors that replicate patient‐specific congenital and disease‐specific phenotypes is an exciting development that promises to enable personalized drug safety evaluation, an approach that has recently been tested in dozens of human induced pluripotent stem cell (iPSC)‐derived cardiomyocytes . Thus, iPSC‐based cardiomyocytes are known to be useful in identifying both congenital and drug‐induced cardiotoxicity hazards, particularly at the individual patient level . However, even within the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative—a global effort among regulators, industry, and academia to develop a mechanistic, model‐informed approach to cardiac safety that includes iPSC‐derived cardiomyocytes as a key component—clinical testing for QT prolongation through in vivo electrocardiogram monitoring in phase I clinical trials remains a key component …”

“…18,19 Thus, iPSC-based cardiomyocytes are known to be useful in identifying both congenital and drug-induced cardiotoxicity hazards, 17,20,21 particularly at the individual patient level. 22,23 However, even within the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative-a global effort among regulators, industry, and academia to develop a mechanistic, model-informed approach to cardiac safety that includes iPSCderived cardiomyocytes as a key component-clinical testing for QT prolongation through in vivo electrocardiogram monitoring in phase I clinical trials remains a key component. 24 The success of applying C-QTc modeling to clinical QT prolongation, along with the potential for iPSC-derived cardiomyocytes to recapitulate in vivo effects, suggests that there may be potential in combining the two approaches in a preclinical setting.…”

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

“…Because hiPSCs capture the genetic Publications on heart regeneration were manually excluded. References from some of the most comprehensive reviews of the field [8,13,62,87] were screened and manually added when not present in the abovementioned search. All the References were then screened and classified according to the control used.…”