# Targeting the genotype to phenotype link in HCM as a therapeutic strategy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $583,290

## Abstract

Ventricular arrhythmia and sudden cardiac death (SCD) is a prevalent complication of hypertrophic
cardiomyopathy (HCM) especially in young adults. Pathogenic variants of sarcomeric protein genes
cause about half of inherited HCM and about a third of sporadic HCM. Little is known, however, about
how sarcomeric protein variants lead to arrhythmia and sudden cardiac death. There is a major unmet
need for a better understanding of disease mechanisms in order to predict patients at risk for SCD and
design mechanism-based therapeutics.
To address this gap, we will apply high throughput functional genomics to identify individual protein
components of arrhythmogenic signaling, and establish their function using in vitro studies in iPSC-
derived cardiomyocytes (iPSC-CMs) and in vivo studies in HCM mutant mice. We will begin by
generating functional genomics probes of the intracellular arrhythmogenic signaling in iPSC-derived
cardiomyocytes carrying HCM causative variants in MYBPC3, MYH7 and TNNT2. The probes will be
identified based on screening synthetic miRNAs (syn-miRs) which collectively suppress nearly all
proteins in the cell and therefore make ideal probes of complex biology. Analysis of probe selectivity
for gene variants will indicate the existence of common and/or distinct signaling mechanisms. In parallel,
we will identify and characterize candidate pathways indicated from analysis of myectomy samples
from MYBPC3 mutant HCM patients. Once we have obtained pathway information and probes from
these two approaches, we will comprehensively determine the protein mediators by high throughput
functional evaluation in the MYBPC3 mutant iPSC-CMs. Based on the effect in the iPSC-CMs,
selectivity for MYBPC3 and potential as a drug target, we will prioritize the most promising candidate
targets for in vivo evaluation by AAV9 knockdown in HCM transgenic mice carrying a Mybpc3 mutation
homologous to that in the iPSC-CMs. We expect that modulating the function of the candidate
mediators will suppress arrhythmia and tachycardia in the Mybpc3 mutant mice.
In summary, these studies will increase our understanding of the arrhythmogenic signaling caused by
HCM mutations and promote the development of improved prognostic and mechanism-based
therapeutics for familial HCM patients. It will also increase our understanding of fundamental
cardiomyocyte biology that might underlie other cardiac diseases. The Specific Aims are: 1) Determine
if discrete signaling mechanisms cause arrhythmic susceptibility across “high” propensity HCM gene
variants, and 2) Comprehensively define the proteins that dictate electrical remodeling by functional
screening in MYBPC3 mutant iPSC-CMs and test their efficacy as therapeutic targets in an Mybpc3
mutant mouse model of HCM.

## Key facts

- **NIH application ID:** 10576285
- **Project number:** 5R01HL152055-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARK MERCOLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $583,290
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10576285

## Citation

> US National Institutes of Health, RePORTER application 10576285, Targeting the genotype to phenotype link in HCM as a therapeutic strategy (5R01HL152055-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10576285. Licensed CC0.

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