# Multi-scale modeling of inherited pediatric cardiomyopathies

> **NIH NIH UH3** · HARVARD UNIVERSITY · 2020 · $1,273,194

## Abstract

Project summary
 The goal of this proposal is to advance in vitro modeling of human heart disease using genome-edited and
patient-derived iPSCs, to use these models to gain new insights into disease pathogenesis, and to develop
new therapeutic strategies. We focus on three monogenic cardiac diseases, Barth syndrome (BTHS), cate-
cholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic cardiomyopathy (ACM; also
known as arrhythmogenic right ventricular cardiomyopathy/dysplasia). These disorders represent major
classes of inherited heart disease, namely disorders of cardiac rhythm (CPVT; ACM) and contraction (BTHS;
ACM). No targeted therapies are available for these disorders, and current management options are far from
ideal, resulting in tragic deaths or cardiac transplantation. Our studies of these diseases will push the envelope
of in vitro disease models in four principle ways: (1) by refining in vitro systems to better reflect the physiology
of native myocardium; (2) by objectively evaluating the ability of induced pluripotent stem cell-derived
cardiomyocyte (iPSC-CM) models to capture inter-individual variation between patients; (3) by identifying novel
therapies through either improved mechanistic understanding or unbiased screening; and (4) by performing
proof-of-concept “Clinical trials in a dish”, in which responses of engineered cell and tissue models are
compared to responses of mammalian models or patients. In the UG3 Phase, we will develop physiological
assay systems of these three monogenic cardiac diseases (Aim 1). These assay systems will scale from cell
pairs to three dimensional engineered ventricles, providing the range of systems necessary to address
challenges spanning high throughput screening to disease pathogenesis to in vitro “clinical trials”. In the UH3
Phase, we will use the 2D tissues and 3D ventricles to discover novel treatments through screens and
mechanistic studies (Aim 2). We will use the 3D ventricles to perform “Clinical trials in a dish” (Aim 3), to
determine the extent to which iPSC-based models capture inter-individual variation and to measure the
therapeutic responses of a panel of patient microphysiological models. Our vertically integrated,
multidisciplinary approach will bring together cardiac biologists, bioengineers, bioinformaticians, and clinicians
to advance the state of the art for in vitro cardiac disease modeling. The impact will extend well beyond the
three rare diseases directly studied by improving cardiac disease models and providing data on the usefulness
of iPSC-CMs for capturing individual patient phenotypes. Creation of in vitro models of normal human organs
would also greatly expedite drug development, by increasing the precision and speed of drug safety testing.
Our deliverables include advances in iPSC-CM differentiation; novel bioengineered systems to assay iPSC-CM
physiological properties; new insights into the pathogenesis of three representative cardiac disease...

## Key facts

- **NIH application ID:** 9995565
- **Project number:** 5UH3HL141798-04
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** KEVIN KIT PARKER
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,273,194
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995565

## Citation

> US National Institutes of Health, RePORTER application 9995565, Multi-scale modeling of inherited pediatric cardiomyopathies (5UH3HL141798-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995565. Licensed CC0.

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