Project summary
Build and validate a screening workflow and accompanying software that can be incorporated into preclinical safety screening pipelines for more accurate allocation of cardiovascular safety liabilities and increase the output of new drugs to benefit patients.
What is the issue for NSW?
Before new drugs come to market, we need to ensure that they not only work, but they are safe. It is well known that drugs that unintentionally block the hERG ion channel in the heart can cause fatal cardiac rhythm disorders. This is a major problem for development of new therapeutics since it is estimated up to 70% of all compounds can bind to hERG channels. Consequently, testing for block of hERG as well as prolongation of action potential duration is a mandatory part of preclinical development.
This approach has been effective in that no new dangerous drugs have come to market since they have been in place. However, there is widespread agreement that this measure is not specific, resulting in false positive results that have led to premature termination of potentially valuable therapeutics that could prolong or enhance the quality of patient’s lives. The economic implications are also huge, with around $5 billion per annum spent on these screens.
The shortcomings of current methods are that they rely on measures that are poor surrogates for risk that are not mechanistically linked to arrhythmias. We propose that rather than analysis of the duration of repolarisation, that the shape of the cardiac action potential is a much richer source of information about underlying electrophysiology, and that subtle changes in this shape precede the emergence of the irregular activity that triggers arrhythmias.
What does the research aim to do and how?
In this study we will test the hypothesis that parameters extracted from quantitative analysis of the shape of action potentials recorded from stem cell derived cardiomyocytes can more accurately predict drug-induced arrhythmia than changes in repolarisation duration. We will build and validate a screening workflow and accompanying software that can be incorporated into preclinical safety screening pipelines that will permit more accurate allocation of cardiovascular safety liabilities and increase the output of new drugs to benefit patients.
The project will leverage the technology infrastructure in the Victor Chang Innovation Centre, which was recently established with a $25 million investment from NSW Health. As part of the iPSC phenotyping core facility we have installed robotic, automated platforms for culture and differentiation of iPSC and functional characterisation of iPSC derived cardiomyocytes. We are the only facility in Australia with access to these combined enabling technologies that will be built on to develop drug screening infrastructure and establish NSW as an internationally recognised centre for safety pharmacology.