Cardiac Repolarization and Stem Cells: An Emerging Path Toward Precision Medicine

Induced pluripotent stem cells (iPSCs) offer an unprece-dented opportunity to study human physiology and disease at the cellular level. They also have the potential to be leveraged in the practice of precision medicine, for example, personalized drug testing. This statement comprehensively describes the provenance of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and strategies through which to promote their wider use for biomedical applications. Human iPSCs exhibit properties that render them uniquely qualified as model systems for studying human diseases: they are of human origin, which means they carry human genomes; they are pluripotent, which means that in principle, they can be differentiated into any of the human body’s somatic cell types; and they are stem cells, which means they can be expanded from a single cell into millions or even billions of cell progeny. iPSCs offer the opportunity to study cells that are genetically matched to individual patients, and genome-editing tools allow introduction or correction of genetic variants. Initial progress has been made in using iPSCs to better understand cardiomyopathies, rhythm disorders, valvular and vascular disorders, and metabolic risk factors for ischemic heart disease. This promising work is still in its infancy. Similarly, iPSCs are only just starting to be used to identify the optimal medications to be used in patients from whom the cells were derived. This statement is intended to (1) summarize the state of the science with respect to the use of iPSCs for modeling of cardiovascular traits and disorders and for therapeutic screening; (2) identify opportunities and challenges in the use of iPSCs for disease modeling and precision medicine; and (3) outline strategies that will facilitate the use of iPSCs for biomedical applications. This statement is not intended to address the use of stem cells as regenerative therapy, such as transplantation into the body to treat ischemic heart disease or heart failure.

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Genome Editing Redefines Precision Medicine in the Cardiovascular Field

Stem Cells International ◽

10.1155/2018/4136473 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Elda Dzilic ◽

Harald Lahm ◽

Martina Dreßen ◽

Marcus-André Deutsch ◽

Rüdiger Lange ◽

...

Keyword(s):

Stem Cells ◽

Regenerative Medicine ◽

Precision Medicine ◽

Genome Editing ◽

Pluripotent Stem Cells ◽

New Technologies ◽

Basic Research ◽

Disease Modelling ◽

Ethical Implications ◽

Regenerative Therapies

Genome editing is a powerful tool to study the function of specific genes and proteins important for development or disease. Recent technologies, especially CRISPR/Cas9 which is characterized by convenient handling and high precision, revolutionized the field of genome editing. Such tools have enormous potential for basic science as well as for regenerative medicine. Nevertheless, there are still several hurdles that have to be overcome, but patient-tailored therapies, termed precision medicine, seem to be within reach. In this review, we focus on the achievements and limitations of genome editing in the cardiovascular field. We explore different areas of cardiac research and highlight the most important developments: (1) the potential of genome editing in human pluripotent stem cells in basic research for disease modelling, drug screening, or reprogramming approaches and (2) the potential and remaining challenges of genome editing for regenerative therapies. Finally, we discuss social and ethical implications of these new technologies.

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Functional Impact of BeKm-1, a High-Affinity hERG Blocker, on Cardiomyocytes Derived from Human-Induced Pluripotent Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21197167 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7167

Author(s):

Stephan De Waard ◽

Jérôme Montnach ◽

Barbara Ribeiro ◽

Sébastien Nicolas ◽

Virginie Forest ◽

...

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Cell Model ◽

Scorpion Venom ◽

Calcium Handling ◽

Cardiac Repolarization ◽

Outer Face ◽

Drug Induced ◽

Induced Pluripotent

IKr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go-Related Gene (hERG, Kv11.1) potassium channels. The blockage of these channels by pharmacological compounds is associated to drug-induced long QT syndrome (LQTS), which is a life-threatening disorder characterized by ventricular arrhythmias and defects in cardiac repolarization that can be illustrated using cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs). This study was meant to assess the modification in hiPS-CMs excitability and contractile properties by BeKm-1, a natural scorpion venom peptide that selectively interacts with the extracellular face of hERG, by opposition to reference compounds that act onto the intracellular face. Using an automated patch-clamp system, we compared the affinity of BeKm-1 for hERG channels with some reference compounds. We fully assessed its effects on the electrophysiological, calcium handling, and beating properties of hiPS-CMs. By delaying cardiomyocyte repolarization, the peptide induces early afterdepolarizations and reduces spontaneous action potentials, calcium transients, and contraction frequencies, therefore recapitulating several of the critical phenotype features associated with arrhythmic risk in drug-induced LQTS. BeKm-1 exemplifies an interesting reference compound in the integrated hiPS-CMs cell model for all drugs that may block the hERG channel from the outer face. Being a peptide that is easily modifiable, it will serve as an ideal molecular platform for the design of new hERG modulators displaying additional functionalities.

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Clinical Trial in a Dish

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314695 ◽

2021 ◽

Vol 41 (3) ◽

pp. 1019-1031

Author(s):

Chi Keung Lam ◽

Joseph C. Wu

Keyword(s):

Stem Cells ◽

Adverse Effects ◽

Induced Pluripotent Stem Cells ◽

Precision Medicine ◽

Pluripotent Stem Cells ◽

Financial Burden ◽

Patient Specific ◽

Drug Induced ◽

Clinical Issue ◽

Induced Pluripotent

Drug-induced cardiotoxicity is a significant clinical issue, with many drugs in the market being labeled with warnings on cardiovascular adverse effects. Treatments are often prematurely halted when cardiotoxicity is observed, which limits their therapeutic potential. Moreover, cardiotoxicity is a major reason for abandonment during drug development, reducing available treatment options for diseases and creating a significant financial burden and disincentive for drug developers. Thus, it is important to minimize the cardiotoxic effects of medications that are in use or in development. To this end, identifying patients at a higher risk of developing cardiovascular adverse effects for the drug of interest may be an effective strategy. The discovery of human induced pluripotent stem cells has enabled researchers to generate relevant cell types that retain a patient’s own genome and examine patient-specific disease mechanisms, paving the way for precision medicine. Combined with the rapid development of pharmacogenomic analysis, the ability of induced pluripotent stem cell-derivatives to recapitulate patient-specific drug responses provides a powerful platform to identify subsets of patients who are particularly vulnerable to drug-induced cardiotoxicity. In this review, we will discuss the current use of patient-specific induced pluripotent stem cells in identifying populations who are at risk to drug-induced cardiotoxicity and their potential applications in future precision medicine practice. Graphic Abstract: A graphic abstract is available for this article.

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