JASON T. MAYNES

Measuring cardiac cell contraction to identify new therapies and predict cardiac toxicity

 

Competition: EXPLORE Program 2015
Funding: $300,000 / 2 years
Beginning: April 2016

Current therapies for heart failure primarily relieve disease symptoms, but most fail to correct the underlying organ dysfunction. New therapies, which are able to target and improve cardiomyocyte function, are challenging to develop, owing significantly to the complex functions of heart muscle and the difficultly in modeling heart cell behavior. The same problems underlie the difficulty in assessing cardiotoxic side effects of drugs, creating expensive late phase drug attrition and potential harm to patients. The need to better predict how drugs will affect the heart to develop safe non-cardiology drugs and new cardiac therapeutics has created an impetus to develop assays that measures the comprehensive functions of cardiomyocyte.

The team proposes to develop the first system able to measure the three main parameters of heart cell functions, by simultaneously measuring the cardiomyocyte beat rate, beat rhythm and most importantly, contraction forces, which has proved very challenging in the past. The team will achieve this feat by culturing human cardiomyocytes derived from induced pluripotent stem cells (iPS) on functionalized polymeric/silicone membranes fitted in 96 well plates and embedded with carbon-nanotube composite stress sensors. The forces created by cardiomyocyte contraction upon addition of drugs will cause the thin polymeric membrane to deform, altering the strain-dependent electrical resistance in the nanotube sensor. Monitoring the stress induced over time will allow for measurements of cardiomyocyte beat rate, rhythm and contractility. Importantly, the device will quantify force measurements from all cells in all directions, a significant limitation of current devices that measure contraction on a single/few cardiomyocytes. The system will be validated by testing known toxic compounds and benchmarked against the current gold standard assay. The team will also test therapeutic drugs on iPS-derived cardiomyocytes from patients with heart failure from hypertrophic and dilated cardiomyopathy, demonstrating how disease effects can be quantified and novel therapies screened for effects on the cardiac tissue.

Jason T. Maynes

Hospital for Sick Children

Co-Investigators

Robert Hamilton
Hospital for Sick Children

Yu Sun
University of Toronto