Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Luca Sala, Milena Bellin, Christine L. Mummery (Corresponding Author)

Research output: Contribution to journalReview articleAcademicpeer-review

36 Citations (Scopus)
73 Downloads (Pure)

Abstract

Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro-arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC-CM-based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine. Linked Articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.

Original languageEnglish
Pages (from-to)3749-3765
Number of pages17
JournalBritish journal of pharmacology
Volume174
Issue number21
DOIs
Publication statusPublished - 1 Nov 2017

Fingerprint

Pluripotent Stem Cells
Cardiac Myocytes
Pharmacology
Safety
Cardiac Arrhythmias
Drug Discovery
Pharmaceutical Preparations
Guidelines
Precision Medicine
Drug-Related Side Effects and Adverse Reactions
Ion Channels
Animal Models
Heart Failure
Cardiotoxicity
Clinical Trials
Cell Line
Research

Cite this

@article{3b18eb419dee4a7ea74a752d7e1a2c49,
title = "Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?",
abstract = "Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro-arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC-CM-based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine. Linked Articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.",
author = "Luca Sala and Milena Bellin and Mummery, {Christine L.}",
year = "2017",
month = "11",
day = "1",
doi = "10.1111/bph.13577",
language = "English",
volume = "174",
pages = "3749--3765",
journal = "British journal of pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "21",

}

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology : has the time come? / Sala, Luca; Bellin, Milena; Mummery, Christine L. (Corresponding Author).

In: British journal of pharmacology, Vol. 174, No. 21, 01.11.2017, p. 3749-3765.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology

T2 - has the time come?

AU - Sala, Luca

AU - Bellin, Milena

AU - Mummery, Christine L.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro-arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC-CM-based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine. Linked Articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.

AB - Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro-arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC-CM-based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine. Linked Articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.

UR - http://www.scopus.com/inward/record.url?scp=84988358048&partnerID=8YFLogxK

U2 - 10.1111/bph.13577

DO - 10.1111/bph.13577

M3 - Review article

VL - 174

SP - 3749

EP - 3765

JO - British journal of pharmacology

JF - British journal of pharmacology

SN - 0007-1188

IS - 21

ER -