InoCardia: Novel human-cell based assay for assessment of cardiovascular liability

Project overview

Adverse effect of drugs on the cardiovascular system is a major cause for compounds failing in both non-clinical and clinical studies. Indeed, some of these adverse effects may only be currently detected after the compound has been granted marketing approval and many thousands of patients treated. Thus such effects represent a significant issue for human health and very high costs for the pharmaceutical industry. Although adverse drug effects on the cardiovascular system may be due to many effects, one area of great concern is the effect of drugs on the force of contraction of the heart. Some drugs can reduce the force of contractions and cause symptoms similar to heart failure in susceptible patients whilst others can increase it resulting in an imbalance between the amount of oxygen needed by the heart and that supplied by the blood.

Currently, testing for drug effects on the force of contraction of the heart is very much dependent on the use of animals (in-vivo tests) and/or low throughput assays using isolated tissues (in-vitro tests). Given the nature of these studies testing is often conducted very late in the drug discovery process. Furthermore, the predictive value of the available tests for human risk is limited. Thus, there is a need for more predictive assays with much greater throughput that can be used to select compounds with much less effect on the heart.

The goal of this project is to test the concept of a higher throughput functional cardiac cell contractile assay under truly physiological conditions. It will essentially advance the information on how the heart behaves functionally and enable us to test inotropic drugs in these conditions. If successful, we aim to develop a higher throughput assay to test many compounds per week enabling selection of compounds for clinical trials that have less liability to adversely affect the contractility of the heart.

Project objectives

When drugs/chemicals are developed to treat a particular disease or for human use purposes they sometimes have side effects that cause damage to the heart. Occasionally these dangerous side effects are only recognised after the drug/chemical has been marketed and taken/used by thousands of people.This is a significant risk to human health and is costly to the pharmaceutical industry when a dangerous product is withdrawn from market. Although side effects of drugs can be caused by many things, one area of great concern is the effects of drugs on the force that heart muscle can produce during its role in pumping blood around the body.

Current drug testing relies on the use of animals such that often the tests do not do well in predicting the effect on humans. Development of a human heart-cell contractility assay would greatly improve the understanding of the human relevance of non-clinical findings; a chemical might cause a change in cardiac contractility in animals, but not humans and vice versa. We aim to develop a test that uses human heart cells in a way that can efficiently test many drugs/chemicals used in high-value industries and reduce the risk of causing any damage to the heart.