# Utilizing Patient-Specific hiPSC-CMs to Investigate Pediatric Calmodulinopathy

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2022 · $41,965

## Abstract

PROJECT SUMMARY/ABSTRACT
Pediatric calmodulinopathy is a life-threatening cardiac arrhythmia syndrome resulting from a single
heterozygous mutation in any of three calmodulin (CaM) genes. Most (68%) persons with a pathogenic CaM
variant will experience a major arrhythmic event such as aborted cardiac arrest or sudden cardiac death by the
age of five years. Calmodulinopathies result in heterogenous clinical features with the two predominant clinical
phenotypes being long QT syndrome (CALM-LQTS) and catecholaminergic polymorphic ventricular tachycardia
(CALM-CPVT). Despite current treatments, 56% of calmodulinopathy patients experience breakthrough cardiac
events, underscoring the need for improved therapeutics. A current barrier to effective treatment is our
incomplete understanding of how calmodulin genetic variants contribute to pathologic phenotypes. Human
induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes (hiPSC-CMs) while
maintaining the patient’s genetic background. Application of hiPSC-CMs in the context of this disease allows us
to better understand patient-specific heterogeneity at the cellular level. In this study, we will establish a CALM-
LQTS hiPSC-CM model using hiPSCs generated from five persons with a pathogenic CaM variant who present
with CALM-LQTS. We hypothesize that we can model a CALM-LQTS phenotype using patient-specific hiPSC-
CMs, identify clinically appropriate drugs that correct it, and determine underlying mechanisms that drive this
phenotype. We will first determine the cellular CALM-LQTS phenotype using blinded electrophysiological,
contractility, and calcium imaging studies and then screen a panel of FDA-approved drugs to identify candidates
that alleviate this phenotype. We will then perform experiments to identify underlying mechanisms that drive the
cellular CALM-LQTS phenotype. We will first determine the contribution of calcium cycling dysregulation, the
primary mechanism of calmodulinopathy, in our CALM-LQTS hiPSC-CM model. We will then leverage this model
to investigate CALM wildtype and variant allele expression levels to determine if allelic imbalance is contributing
the cellular CALM-LQTS phenotype. We will also assess the pathogenicity of each variant on the cellular
phenotype by using genome editing. Phenotyping of these edited lines will allow us to determine if these variants
are necessary and sufficient for the cellular CALM-LQTS phenotype. Successful completion of these aims will
provide a patient-specific methodology to identify necessary clinical treatments for CALM-LQTS and elucidate
the drivers of this rare and severe disease. Through the support of their sponsor and their established training
plan, the predoctoral fellowship applicant will develop expert knowledge in the field and the necessary skills in
experimental design, analysis, communication, and technical techniques to complete this research strategy and
transition to the next stage of their translational me...

## Key facts

- **NIH application ID:** 10520006
- **Project number:** 5F31HL156596-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Katherine Ashley Fetterman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,965
- **Award type:** 5
- **Project period:** 2020-12-10 → 2022-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520006

## Citation

> US National Institutes of Health, RePORTER application 10520006, Utilizing Patient-Specific hiPSC-CMs to Investigate Pediatric Calmodulinopathy (5F31HL156596-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10520006. Licensed CC0.

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