To generate a physiologically-relevant contractility platform with cells that are phenotypically ‘mature’, possess a robust contractile apparatus, move calcium between intracellular and extracellular spaces and metabolically generate substantive amounts of energy.
Cardiovascular (CV) safety liabilities are one of the most common causes of drug attrition in both the nonclinical and clinical setting. These liabilities manifest in a variety of ways that include structural injuries and derangements in CV function. Changes in contractility may lead to clinical heart failure and even death. Important classes of drugs, such as anti-neoplastic tyrosine kinase inhibitors, are currently facing particular safety challenges with this effect.
iPS cell-derived cardiomyocytes (iPSC-CMs) have shown early promise for replacing animal use in cardiovascular research and many pharmaceutical companies and academic researchers are developing assay platforms to identify potential electrophysiological and structural liabilities earlier in development (i.e. ‘pre-animal’). A similar capability for contractility assessments would be very useful from a scientific and 3Rs perspective.
Historically, there has been a heavy reliance on highly invasive, technically demanding, surgically instrumented telemetered animal models in preclinical studies that provide indirect measures of contractility in vivo. More recently, imaging (e.g. echocardiography) has been used as an investigative and mechanistic tool both preclinically and clinically but it is low throughput and labour intensive. The only in vitro/ex vivo models that are available are perfused whole heart models from animals and isolated cardiac cells from animals and humans. There is no currently validated/qualified human-derived in vitro system for assessing drug-induced changes in contractility under varying levels of physiologic load.
The ability to study changes in cardiac contractility in vitro would allow the investigation of potential causes of long QT syndrome that are both hERG and non-hERG dependent. This would allow a more accurate prediction of potential drug-induced cardiac toxicity in preclinical and clinical settings; thus help to reduce attrition. Mechanistic understanding of changes in cardiac contractility from in vitro models would also be relevant to efficacy studies earlier in the drug discovery process.
The rapid development of human iPS cell technologies and materials sciences provides an opportunity to develop a dynamic, human-relevant assay system to screen and characterize novel drug candidates for cardiac contractility liabilities. Recent publications have demonstrated that the extracellular matrix, morphology and orientation of cardiac cells are important for cardiac contractility and calcium signalling in cardiac myocytes and there have been significant advances in substrates for monitoring contractile tension.However, there is the need for a robust in vitro model that reflects the 3D architecture of cardiac tissue with mature cell phenotypes.
- Assessment of developmental drug pre-candidates on cardiac contractility relies exclusively on the use of animals prior to clinical trials. A typical study uses 12 to 24 dogs
- A physiologically relevant 3D in vitro model will replace the use of animals in these studies and reduce the number of animals needed to assess the mechanism of action of any drug-induced effect
- An in vitro system where load can be adjusted to model the pathophysiology of disease tissue could also be used to reduce animal use in efficacy studies. A typical efficacy study uses approximately 24 mice
- Once validated, an in vitro platform could be used to screen compounds and provide earlier go/no-go decisions hence reducing the number of animals used to test compounds that would ultimately fail in development.
Phase 1 winners
Project teams led by:
- Professor Chris Denning, University of Nottingham, £100,000.
- Professor Cesare Terraciano, Imperial College London, £99,958.
- Professor Wolfram Zimmerman, University Medical Center Göttingen, £100,000.
Phase 2 winner
Project team led by: