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Tuesday, October 22 • 11:30am - 11:50am
Advances in Imaging and Analysis- Development of a Multiparametric Structural Cardiovascular Toxicity Imaging Assay Using iPSc Derived Cardiomyocytes

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According to Laverty and co-workers (2011), 27% of drugs fail to reach phase I due to cardiovascular liability and up to 45% of drug withdrawals post approval are due to cardiovascular toxicity. The majority of these withdrawals were due to the induction of arrythmia in patients which led to various initiatives by regulatory agencies such as the comprehensive in vitro proarrhythmia assay (CiPA) initiative by the FDA which utilise functional assessments of human iPSc derived cardiomyocytes to predict potential acute cardiovascular liabilities. However, these approaches cannot capture the effects of compounds with a chronic dosage regimen that are capable of causing structural changes in cardiac cells.

The aim of this project is to develop an in vitro assay capable of flagging compounds with potential cardiovascular liabilities when applied chronically using iPSc derived cardiomyocytes. In order to capture the multivariate potential mechanisms of toxicity, cells were measured to assess a number of different functional and structural parameters, such as calcium flux, contraction, viability, mitochondrial membrane potential as well as actin organisation. The use of 3D co-culture models was also assessed as these are postulated in the literature to increase the maturity and, therefore, the physiological relevance of the model.

The approach generated data from numerous parameters describing both kinetic and imaging readouts, requiring customised data analysis solutions. This brought the challenge to balance the need to test compounds rapidly in high throughput (384-well) at early lead identification and lead optimisation stages of drug development, with the desire to generate rich datasets informative of underlying mechanisms of structural cardiotoxicity.

Assay predictivity was assessed using annotated diverse compound sets including both proprietary and public domain compounds known to induce structural cardiotoxicity in vivo.

Authors:
Ellie Handford, GSK
Peter Clements, GSK
Andrew Brown, GSK
Jo Francis, GSK

Speakers
avatar for William Stebbeds, Ph.D.

William Stebbeds, Ph.D.

Senior Scientist, GSK
Senior scientist at GSK specializing in developing novel assays for drug discovery and development using complex in vitro models and multi-parametric analysis

Chair

Tuesday October 22, 2019 11:30am - 11:50am
Wellcome Auditorium