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Fully automated, high-throughput screening for drug discovery using hiPSC-derived Cardiomyocytes

24 July, 2018

Adverse off-target effects of drug candidates pose a critical challenge to the development of safe therapeutics. Financial and ethical issues resulting from limitations in current safety pharmacology methods, such as lack of accessible high-throughput solutions, have led to the delay of studies to late stage of preclinical development. This increases the risk of costly late stage failure of candidate drugs.

A major cause of high drug-attrition rates is missed cardiac toxicity, in particular at later stages of development, which can manifest in serious conditions, such as proarrhythmia and heart failure. Availability of in vitro models correlating with clinical results and effective preclinical toxicity screening assays are key to reducing drug-attrition rates.

Human induced pluripotent stem cell (hiPSC) cardiomyocytes have over the past decades been established as a viable platform for safety pharmacology. In combination with high throughput screening automation, stem cell technology shows huge promise for enabling early detection of cardiac toxicity in drug discovery. The utility of hiPSC-based cellular models in combination with automated phenotypic screening can enable reliable safety and efficacy testing of drugs early in the development stage, revolutionizing the drug discovery and development process.

Ncardia has established a menu of automated and scalable assays that utilize iPSC-derived Pluricyte® Cardiomyocytes in a 384-well microplate format. These assays enable automated screening of tens of thousands of potential compounds in a physiologically relevant model for high throughput efficacy screening. Fully automated plate handling, cell seeding and maintenance has been established in an automated liquid handling workstation.

 

Figure 1: High throughput screening automation robot.

Automated, high-throughput screening of hiPSC-derived cardiomyocytes enables a more cost-efficient drug discovery process. For example, it facilitates early cardiac safety screening, even before traditional hERG assays are executed. Consequently, the risk of costly late stage failures due to cardiac safety are reduced. For this purpose, high throughput safety assays (e.g. Ca2+-transient assays in 384 wells format) were developed and validated for predictivity and reproducibility. Additionally, dedicated high-throughput assays have been developed for specific disease hiPSC’s and exploited for highly-predictive screening of compound efficacy.

Predictivity and reproducibility are key. That’s why Ncardia is actively engaged in innovating higher throughput assays to enable efficient and effective testing of more compounds earlier in the drug discovery process using comprehensive hiPSC-based models.

Current development efforts have set the basis for further miniaturization in a 1536-well format. With Ncardia's standardized services and validated cell models we will see an increase in throughput and decrease in costs of drug screening in drug discovery and development.

Further reading

Gintant G, Fermini B, Stockbridge N, Strauss D. The Evolving Role of Human iPSC-Derived Cardiomyocytes in Drug Safety and Discovery. Cell Stem Cell Forum, Vol. 21, 1, P14 – 17 (2017)

Hutchinson L, Kirk R. High drug attrition rates—where are we going wrong? Nature Reviews Clinical Oncology – Editorial. Vol. 8, P 189-190 (2011)

Mordwinkin NM, Burridge PW, Wu JC. A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards. J Cardiovasc Transl Res. Vol. 6, 1, P 22 – 30 (2013)

Picture reference: https://www.ppscreeningcentre.com/wp-content/uploads/2017/10/robot-full-cmyk.jpg

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