Induced pluripotent stem cells (iPSCs) hold the promise of enhancing precision diagnosis and treatment for cardiovascular diseases such as inherited arrhythmias. However, a number of hurdles currently hinder realization of this promise, including (1) clinically relevant arrhythmais are the emergent properties of tissues, but physiological assessment of iPSC-CMs is mostly limited to single cell assays; and (2) the fundamental assumption that inter-individual differences in disease severity or in drug responses will be recapitulated in iPSC-CM models remains untested. In this proposal, a collaborative, multidisciplinary team of clinicians, cardiovascular biologists, and bioengineers will address these hurdles to advance the state-of-the-art in arrhythmia modeling. The team will develop patient-derived and genetically engineered iPSCs-CMs, assemble them into bioengineered tissues, assess their arrhythmia susceptibility using an optogenetic stimulation and recording system, and compare these data to clinical data on the patients. We will focus our efforts on Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a highly malignant ventricular arrhythmia predominantly caused by mutation in the cardiac Ryanodine receptor (RYR2), the major intracellular calcium release channel. Specifically, we propose the following specific aims: Aim 1. To model the generation of arrhythmias in CPVT using engineered heart tissue and a purely optical stimulation and recording platform. Aim 2. To compare the anti-arrhythmic response of CPVT patients and their iPSC-CMs to flecainide therapy. Aim 3. To use the in vitro iPSC-CM CPVT model to evaluate mechanisms by which RYR2 mutation leads to ventricular tachycardia. This proposal will advance the state-of-the-art in developing patient-specific models of inherited arrhythmia by developing an engineered heart tissue disease model and using it to evaluate the extent to which these models recapitulate clinical differences between patients.
|Program type||Collaborative Sciences Award|
|Effective start/end date||07/01/2016 → 06/30/2019|