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At the end of the day, drug approval for commercialisation is about benefits outweighing potential side effects and, most importantly, ensuring that serious complications are avoided – quite literally – at all costs. But despite all efforts made to avoid such scenarios, adverse drug reactions are still the fifth cause of deaths in the EU.
Cardiac complications are particularly high on the list of adverse effects to rule out before drug commercialisation, but that didn’t prevent hundreds of drugs being associated with such effects and withdrawn from the market over the past 60 years. The pharmaceutic industry is under pressure to provide more reliable assessments, but current technologies and methodologies still have their shortcomings.
The EU-funded MAREP project, which was supported by the European Research Council (ERC), aims to address these. “The MAREP platform combines existing commercial Microelectrode Array (MEA) systems with an innovative laser technology,” says ERC grantee Francesco De Angelis. “We exploit ultrashort pulsed lasers and nanoporous electrodes to achieve a highly localised poration of the cellular membrane. This allows for direct contact between the MEA electrode and the inner cellular compartment (the cytosol). In other words, when the cardiac cell fires an action potential, the electrode is able to directly record transmembrane ionic currents.”
To verify the technology’s performance, the team conducted screenings of various models of human-derived cardiomyocytes from human pluripotent stem cells. They used several drugs and compounds from the internationally recognised list released by the Comprehensive in vitro Proarrhythmia Assay (CiPA) consortium.
Multiple benefits
De Angelis was very pleased with the result: “The MAREP technology allowed us to detect, with high precision, all the expected effects of the tested molecules on different cardiac models. Most importantly, we could reach this result by using a very low number of biological specimens and independent tests. We can safely announce that MAREP leads to a substantial reduction of the time and money required to assess the toxicity of a drug on cardiac cells.”
Besides enabling faster and more cost-effective drug testing, the technique’s main advantage is its low invasiveness. The cell membrane poration is so small and transient that the cell membrane can reform in just a few minutes without any permanent damage. This explains why drug safety assessments can be conducted on the same specimens several times after the drug candidate has been administered, while enabling cardiotoxicity assessments spanning several days or weeks.
But that’s not the only benefit. “MAREP also allows for monitoring accurately and simultaneously the electrical signals of a very large number of cardiac cells in 2D syncytia. It combines high-precision and large data sets for statistical significance with strong parallelisation,” De Angelis explains.
Completed in April 2021, MAREP has led to the creation of a start-up – Foresee Biosystems – in charge of commercialisation. The company will build upon the competitive advantage brought by MAREP to commercialise innovative products and services. Foresee Biosystems has received a seed investment of EUR 500 000 from corporate investors and hopes to finalise its main product by the end of 2021 for commercialisation in early 2022. This first product will be a benchtop instrument for research labs and contract research organisations (CROs) active in cardiac electrophysiology and cardiac drug safety.
“We’ve also started the development of a new platform to translate the MAREP technology to high-throughput screenings, which are required by pharmaceutical companies. We will develop and commercialise a MAREP platform with multiwell capabilities, and we will also offer cardiac drug safety screenings as a service,” De Angelis concludes.