New drug discovery relies on several phases of safety assessment. One such prominent in vitro safety assessment assay is the “hERG potassium channel assay” for cardiac safety. If a compound blocks the hERG potassium channel in a cardiomyocyte (cardiac muscle cells), it can cause a delay in the action potential which potentially shows up as an arrhythmia (irregular heartbeat). To check if a compound can cause arrhythmia, genetically modified (hERG transfected) human embryonic kidney cells (hERG-transfected HEK293 cell) and Chinese hamster- ovary cells are used regularly, screening hundreds of compounds eventually. Considering the huge number of compounds being tested by pharmaceutical industries, it is not possible to use human adult cardiomyocytes for these tests. However, though their application is completely standardized, reliability on data generated using non-cardiomyocytes is still a topic under discussion.

Fig. 1. An overview of Cardiac safety assessment in pharmaceutical industry. The figure shows an overview of advantages and limitations associated with the present industry standard- hERG channel assay and the alternative transcriptomic approach proposed.

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) are one of the potential substitutes possessing inherent ion channels comparative to a human cardiomyocyte. When treated with test compounds, the changes occurring in the transcriptome (the complete set of RNA transcripts that are produced by the genome) was studied to identify genomic biomarkers. In other words, these biomarkers/changes in the heart cell’s gene signature can be revealed at a very early stage in the cell in response to a drug treatment. The biomarkers thus proposed can henceforth potentially be used to predict drug-induced cardiotoxicity (including arrhythmia) for a specific class of compounds.

在这项研究中,研究人员提出了一个平底锅官方manbetx手机版el of genes that undergo change when treated with 3 major compounds (doxorubicin, daunorubicin and mitoxantrone) belonging to a class of drugs called anthracyclines. This was achieved using a method called “transcriptomic profiling”. The study showed that hiPSC-CMs treated with doxorubicin showed irregular beating and a certain level of cytotoxicity (cell death). Transcriptomic profiling generated a list of 84 genes which showed significant changes due to doxorubicin treatment. These genes were involved in cardiac contraction, ion regulation, response to DNA damage and stress and apoptosis associated genes. These changes to gene expression were verified using real-time PCR analysis. Parallel studies were
conducted on hiPSC-CMs treated with daunorubicin and mitoxantrone (other anthracycline family members with known cardiotoxicity) to study the changes in expression of these 84 genes using real-time PCR analysis. From the results, the final panel of 35 genes that are commonly influenced by all three anthracycline compounds was generated. Most of the genes on this panel are markers representing cardiac stress and stress response of hiPSCCMs exposed to anthracyclines. Hence the authors conclude that with further research, these 35 genes could act as anthracycline responsive genes helping with the screening of further anthracyclines for cardiac toxicity or as biomarkers for compounds having same mechanism of action as doxorubicin, daunorubicin and mitoxantrone.

Prof. Agapios Sachinidis

Publication

Stem cells and differentiation–a synoptic review of patents granted since 2009.
Sureshkumar P, Srinivasan SP, Natarajan K, Gaspar JA, Hescheler J, Sachinidis A
Expert Opin Ther Pat. 2015 Jun

Read offline:

Related Articles:

	Macrophage-myofibroblast transition: a novel target for…Kidney is one of the major organs in our body for detoxification. Its failure is an important cause of patient mortality that serves as a primary disease and a lethal…
	Prevention of congenital heart anomalies: the secret kept by…CITED2 is a transcriptional modulator involved in the regulation of the expression of many other genes in vertebrates. At very early stages of embryo development, CITED2 is particularly important for…
	The Neuromuscular Junction: a core interpreter in the…Muscle and nerve communicate at the level of a specialized region, namely the neuromuscular junction (NMJ), a synaptic connection where the peripheral nervous system contacts skeletal muscle fibers, governing crucial…
	Sex differences in heart failure outcomes in Ontario, Canada心failure is a leading cause of death in women and men around the world. Despite recent advances in the management of heart failure, much still need to be learned…
	Muscle pain treated with injected normal saline solutionPain comes in all shapes and sizes. Ranging from acute to chronic, from nociceptive and myofascial to neuropathic, pain is a part of life. Myofascial or muscle pain, is among…
	Trends in heart failure diagnosis for women and men in urban…心failure remains a significant cause of death and disability for women and men. It is estimated that 1 in 5 individuals will be diagnosed with heart failure in their…