# Genome Editing Treatment for Catecholaminergic Polymorphic Ventricular Tachycardia

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2021 · $45,877

## Abstract

There is a fundamental gap in treatment for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).
Pharmacological treatment of CPVT is partially effective for a disease that causes sudden death. A fuller
understanding of novel gene editing approaches is needed to develop safe, non-surgical, and effective
therapies that target the underlying causes of CPVT. In approximately 60% of CPVT patients, mutations in
RYR2 cause arrhythmia through abnormal calcium handling in cardiomyocytes. The lab has shown that using
CRISPR/Cas9 to knockdown the RYR2 mutant allele is effective in preventing ventricular tachycardia(VT) by
decreasing expression of dysfunctional RyR2. The overall objective of this application is to improve therapy for
patients with CPVT. Preliminary data generated by the applicant showed that directly targeting a disease-
causing mutation with traditional CRISPR/Cas9 therapy in a CPVT mouse model prevented pacing induced VT
but reduced total expression of RyR2. The central hypothesis of this proposal is that novel methods of
CRISPR/Cas9 gene editing can treat CPVT by specifically correcting causative mutation sites, reducing mutant
RyR2 expression while preserving total RyR2 expression, normalizing Ca2+ handling, and decreasing
susceptibility to VT. The rationale for this research is that an understanding of the effectiveness and specificity
of gene editing in the correcting mutations in the heart may lead to safe novel approaches to treat genetic
cardiac disorders. The hypothesis will be tested with the following specific aims 1) test the therapeutic potential
of human RYR2 mutation correction in an iPSC-CM preclinical model of CPVT and 2) test the therapeutic
potential of mouse RYR2 mutation correction in a mouse model of CPVT. To determine aim 1, we deliver
CRISPR/Cas9 prime editing vectors to IPSC, derive CM, and measure function through confocal and light
sheet imaging of IPSC and 3D cardiac organoids. To determine aim 2, we will use Lenti-CRISPR/Cas9 prime
editing vectors to treat mouse models of CPVT and measure long-term cardiac function through
echocardiography, EKG, programmed electrical stimulation, and molecular analysis. This research is
significant in that it will advance gene editing correction of RYR2 mutations as a safe and effective method for
the treatment of CPVT.

## Key facts

- **NIH application ID:** 10156046
- **Project number:** 1F30HL156669-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Oliver Moore
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $45,877
- **Award type:** 1
- **Project period:** 2021-03-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156046

## Citation

> US National Institutes of Health, RePORTER application 10156046, Genome Editing Treatment for Catecholaminergic Polymorphic Ventricular Tachycardia (1F30HL156669-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10156046. Licensed CC0.

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