An animal-free future for heart research: functional characterisation of novel refined human engineered heart tissue

Helen will characterise the use of human induced pluripotent stem cell derived cardiomyocytes to replace rat cells in an in vitro approach for cardiovascular disease modelling and drug testing. The work builds on two technologies previously developed with NC3Rs funding.

This award was made as part of the 2024 non-animal derived product validation grants supported with funding from the Department for Science, Innovation and Technology (DSIT).

This award aims to combine two technologies previously developed with NC3Rs funding to characterise and validate refined human engineered heart tissue (hEHT) in order to help augment its utility for several applications, including disease modelling and drug testing. This approach addresses the 3Rs leading to the replacement of animal tissue and cells used during the pre-clinical stages of drug discovery and development.

Despite vast expenditure ($2.6Bn) and time to develop a new drug (10-15 years), 93% of all phase I clinical projects still fail. Unexpected cardiovascular side effects (CVS) are the biggest reason projects fail atpre-clinical testing [45%]. In addition to this cardiovascular diseases(CVD) have collectively remained the leading causes of deathworldwide and substantially contribute to loss of health and excesshealth system costs. In the UK, the medical expenses related to CVDs, are estimated to cost the UK health system an estimated £10 billion and the economy an estimated £25 billion a year.

Translational research plays a crucial role in creating new treatments that can lessen the impact of CVD. However, the potential of new therapies has yet to be fully realized. The lack of translation of effective and safe drugs to treat CVD, can be attributed to various factors, of which one significant factor is the inability of many findings from pre-clinical in-vitro cardiac models to be translated into the clinical settings. Current drug testing relies on the use of animals such that often the tests do not predict well the effect on humans.

With signifi ant NC3Rs/InnovateUK funding Professor Helen Maddock and colleagues have previously developed an innovative cardiovascular in-vitro assay called the work-loop model which mimics the synchronised mechanical and electrical events that occur in the heart inside the body (in-vivo), using isolated heart cells and tissue with the aim of reducing the use of animals. This assay has superior predictivity for effects in humans. Dr Katja Grehmlich and colleagues using NC3Rs funding produced novel refined hEHTs, resulting in more mature characteristics that are functionally similar to adult human cardiomyocytes. Working with Co-Investigator Katja and colleagues who developed the refined hEHT, Helen will explore combining the two technologies to augment and support more clinically relevant hEHT studies to be conducted without the use of animals. To demonstrate the utility of the refined hEHTs, Helen and the team will characterise the hEHT behaviour under comprehensive and clinically relevant functional conditions using the work-loop in-vitro assay.