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Expert Insights: iPSC-derived cardiomyocytes for cardiac drug discovery

By Georgios Kosmidis, PhD

What do iPSC-derived cardiomyocytes bring to cardiac disease modeling and drug discovery?

Georgios Kosmidis, PhD,
Senior Scientist at Ncardia
Expert Profile

Dr. Georgios Kosmidis, senior scientist at Ncardia, shares his experience and insights about using induced pluripotent stem cell (iPSC)-derived cardiomyocytes for disease modeling and drug discovery. Georgios obtained his PhD at the Leiden University Medical Center in 2016. During his doctorate studies, Georgios used human iPSC-cardiomyocytes to model cardiac arrhythmias. He has extensive experience in electrophysiology, assay development and the use of human iPSC-cardiomyocytes for the study of compound efficacy and toxicity in high-throughput screenings.

Insights

There has been an impressive decline in deaths from cardiovascular disease over the past 60 years, but its prevalence remains persistently high, and it is the leading cause of death worldwide [1]. Georgios explains that while many pharmaceutical companies are investing a lot of time and money to find better therapies for cardiovascular diseases, several factors hamper the drug discovery process in the cardiac field.

“The attrition rate in clinical trials is particularly high for drugs targeting cardiac diseases. This is partially due to the low predictability of the models used in the early phases of drug discovery. It is also a consequence of the significant difference in treatment responses among patients. And finding the right target to rescue the disease can be quite complex, especially when patients with the same genetic mutation manifest the disease phenotype with diverse severity.”

Advances in human iPSC-derived cardiomyocytes have brought a new in vitro approach that can enhance cardiac disease modeling and drug discovery. iPSC-derived models lead to clinically relevant results much faster than traditional models because they retain patient-specific background and better recapitulate cardiac disease phenotypes. For instance, interspecies differences – such as the fact that mouse heart rate is eight times faster than human – lower the predictive value of animal models. Georgios explains how these are the key reasons to test a compound’s safety and efficacy on iPSC-derived disease models: they can increase the success rate of clinical trials.

“I remember when this technology started 10 to 15 years ago, there was a lot of skepticism in the scientific community. Over the years, though, the experts working with iPSCs have changed that perception by proving the many benefits of bringing human biology to the pre-clinical culture dish. At Ncardia, we have successfully modeled diseases like cardiac hypertrophy, dilated cardiomyopathy, Friedreich’s ataxia and long QT syndrome. We use this experience to enable drug discovery projects with physiologically relevant disease models in high-throughput.”

To generate iPSC-derived cardiomyocytes efficiently and in large-scale, Georgios and the entire scientific team at Ncardia identified and addressed bottleneck points from a technological perspective. They established large-scale manufacturing procedures and developed multiple assays with clinically relevant functional and biomarker readouts at high-throughput. He recognizes that innovation is a team goal to further improve maturation protocols and enable 3D co-culture of multiple cardiovascular cell types at large scale.

“It is time for the pharmaceutical industry to start using more cardiac disease models based on human iPSCs. The benefits along the drug discovery and development process are clear – from more precise target identification to more translational leads that will help reduce the attrition rate and the costs. I believe that patient-derived iPSCs will soon also be used in large-scale for patient stratification during clinical trials and personalized medicine.”

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Reference: [1] Mensah, G. A., Wei, G. S., Sorlie, P. D., Fine, L. J., Rosenberg, Y., Kaufmann, P. G., ... & Gordon, D. (2017). Decline in Cardiovascular Mortality: Possible Causes and Implications. Circulation Research120(2), 366-380 . doi: 10.1161/CIRCRESAHA.116.309115

Case Study
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Modeling cardiac hipertrophy with human iPSC-derived cardiomyocytes for hit identification and validation