# Microphysiology Systems Database Supplement to Tissue Chips for Precision Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia-Supplement

> **NIH NIH UG3** · BOSTON CHILDREN'S HOSPITAL · 2021 · $88,500

## Abstract

SUMMARY
 Therapeutic trials in rare diseases are challenging, particularly those that involve children and therapeutic
choices with potentially life or death consequences. Patient-specific tissue-chip approaches have the potential
to demonstrate therapeutic efficacy without exposing patients to risks associated with experimental therapy or
randomization to the control arm. Moreover, patient-specific tissue-chip approaches may de-risk clinical trials
by optimizing patient selection and inform future clinical trials by elucidating mechanisms that underlie the vari-
ation in patients' therapeutic responses. Achieving these long range goals requires demonstration that patient-
specific tissue-chip platforms accurately predict the therapeutic responses of individual patients. Here we pro-
pose to test the hypothesis that tissue-chips predict therapeutic responses in catecholaminergic polymorphic
ventricular tachycardia (CPVT), a rare inherited arrhythmia and to gather information critical for the design of
future therapeutic trials.
 CPVT is among the most malignant and difficult to treat of the inherited cardiac arrhythmias. A hallmark of
CPVT is ventricular arrhythmia induced by exercise and emotional stress. Despite standard-of-care therapy, in-
cluding β-blockers, implantable cardiac defibrillators (ICDs), or surgical sympathetic cardiac denervation, the
estimated 8 year fatal or near-fatal event rate is ~15%, with death occurring in ~6%. Over the past decade, fle-
cainide has proven to be effective therapy for many CPVT patients, either in combination with β-blocker or as
monotherapy. However, some patients do not respond to flecainide. Mechanisms of non-responsiveness and
predictors of response have not been identified. We have recently reported that CaMKII inhibition is a promis-
ing therapeutic strategy for CPVT, and future therapeutic trials of CaMKII inhibition will likely be performed in
CPVT.
 In the UG3 phase of this proposal, we will recruit patients whose clinical response to flecainide is known,
and generate iPSCs from these patients. At the same time, we will optimize tissue chip platforms to assess ar-
rhythmia risk using patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). In the UH3 phase, we will per-
form two "clinical trials" in a dish: First, in a "retrospective clinical trial" in a dish, we will compare patients'
known flecainide responses to the responses of their iPSC-CMs. Second, we will assess the spectrum of
genotypes where CPVT inhibition is effective, and determine if there are favorable or unfavorable interactions
between CaMKII inhibition and flecainide.
 Together these studies will rigorously test the hypothesis that personalized disease models can predict indi-
vidual patient therapeutic responses and can be used to help plan future clinical trials.

## Key facts

- **NIH application ID:** 10434288
- **Project number:** 3UG3TR003279-02S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** KEVIN KIT PARKER
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $88,500
- **Award type:** 3
- **Project period:** 2020-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434288

## Citation

> US National Institutes of Health, RePORTER application 10434288, Microphysiology Systems Database Supplement to Tissue Chips for Precision Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia-Supplement (3UG3TR003279-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434288. Licensed CC0.

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