# Novel molecular therapies for CPVT

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2020 · $170,165

## Abstract

This proposal describes a five-year training and career development program that will prepare its principle
investigator, Dr. Vassilios Bezzerides, to be an independent investigator in the field of channelopathies and
inherited arrhythmia disorders. This program will build on Dr. Bezzerides’ existing background in cellular and
clinical electrophysiology by providing additional expertise in induced pluripotent stem cells (iPSCs), genome
editing, and translational research techniques. The principal mentor for this program will be Dr. William Pu,
Professor of Pediatrics and Cardiology at Boston Children’s Hospital and Harvard Medical School. Dr. Pu is an
internationally recognized expert in cardiac development and iPSC disease modeling. The enclosed proposal
outlines a comprehensive training program with structured mentorship including an advisory committee with
expertise in cardiovascular research and bioengineering, formal coursework, and a research plan that will
provide rigorous training in disease modeling and novel therapy development. This proposal is focused on the
investigation of novel therapeutic strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT),
a highly malignant inherited arrhythmia disorder characterized by life-threatening ventricular arrhythmias during
times of stress or exercise. Current CPVT therapy is inadequate, with both therapy related toxicity and frequent
treatment failures. Most CPVT cases are caused by mutations in ryanodine receptor type 2 (RYR2), which
encodes the major cardiomyocyte intracellular Ca+2 release channel. Using iPSC-CMs, we developed a novel
engineered human myocardial model (“opto-chip”) of CPVT that reproduces key features of this arrhythmia at a
tissue level. Our preliminary data demonstrates that inhibition of Ca2+/calmodulin kinase II (CaMKII) blocks the
pro-arrhythmic phenotype of CPVT iPSC-CMs. In Aim 1, using pharmacology, genome editing, and engineered
tissues, Dr. Bezzerides will determine if CaMKII inhibition is a broadly applicable by evaluating pathogenic
CPVT genotypes from each of the four canonical pathogenic regions within the RYR2 gene and determine the
degree of inhibition necessary for arrhythmia suppression. In Aim 2, Dr. Bezzerides will further develop CaMKII
inhibition as a clinically applicable therapeutic strategy for CPVT. To refine this strategy Dr. Bezzerides will test
the effectiveness of target CaMKII in the cells of the cardiac conduction system using clinically relevant
outcomes. A positive result would serve as the basis for further study as a step towards a first-in-human trial. In
Aim 3, Dr. Bezzerides will use genome editing, patch clamp, and a second generation opto-chip assay to
dissect the role of late sodium current blockade in the treatment of CPVT. Although controversial, late sodium
current blockade may be the mechanistic basis for flecainide’s efficacy in CPVT. Better understanding of the
mechanism may lead to new therapeutic options with...

## Key facts

- **NIH application ID:** 9961646
- **Project number:** 5K08HL140197-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Vassilios James Bezzerides
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $170,165
- **Award type:** 5
- **Project period:** 2018-07-12 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961646

## Citation

> US National Institutes of Health, RePORTER application 9961646, Novel molecular therapies for CPVT (5K08HL140197-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961646. Licensed CC0.

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