# Pathogenic mechanisms and therapeutics for the cardiac manifestations of myotonic dystrophy type 1

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $431,597

## Abstract

Project Summary / Abstract
Myotonic dystrophy (DM) is the most common cause of adult onset muscular dystrophy and the second
most common cause of muscular dystrophy overall. At least 50% of individuals affected by DM type 1
(DM1) have cardiac involvement, primarily conduction abnormalities and life threatening arrhythmias.
Cardiac involvement is the second leading cause of mortality in DM1 responsible for 25% of disease-related
deaths. The pathogenic cause of DM1 is well established to be toxicity of the expanded CUG repeat-
containing (CUGexp) RNA expressed from the expanded DMPK allele. The CUGexp RNA disrupts RNA
processing, signaling pathways and microRNA regulation. However the specific molecular mechanisms by
which expression of CUGexp RNA in heart tissue causes conduction abnormalities, arrhythmias and
ventricular dysfunction are unknown. Therapeutic approaches applied to DM1 have focused on skeletal
muscle and heart presents a separate set of issues with regard to both the details of disease mechanisms
and therapeutic approaches. We developed a mouse model for tetracycline (tet)-inducible expression of
CUGexp RNA specifically in cardiomyocytes. The tet-inducible transgene expresses 960 interrupted CUG
repeats in the context of a human DMPK genomic segment containing exons 11-15. Expression of CUG960
RNA produces most of the cardiac conduction abnormalities and propensity for the arrhythmias that are
likely to be responsible for cardiac sudden death in DM1. The mice also show robust splicing changes as
observed in DM1 heart tissue. Importantly molecular and electrophysiological abnormalities are reversible
upon shutting off expression of CUG960 RNA. In this project we will use the mouse model to identify and test
hypotheses for the molecular basis for heart pathogenesis in DM1 and apply novel therapeutic approaches.
The goal of the first aim is to use in vivo and ex vivo electrophysiological analyses in combination with
detailed analyses of intracellular structure, transcriptome and signaling changes to identify the basis for the
cardiac manifestations induced by CUG960 RNA. The key results will be tested in DM1 tissue samples for
validation. The second aim is to use genetic rescue of the cardiac features to test hypothesized disease
mechanisms, and with the expectation that multiple mechanisms contribute to pathogenesis, to determine
the contributions of different mechanisms. The third aim is to apply approaches using deactivated Cas9 to
target CUG960 RNA for transcriptional or post-transcriptional downregulation. Upon completion of this project
we anticipate having an understanding of the molecular and physiological pathways linking CUGexp RNA to
cardiac dysfunction and to have optimized a therapeutic approach to reverse DM1 cardiac features.

## Key facts

- **NIH application ID:** 9915976
- **Project number:** 5R01HL147020-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas A Cooper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,597
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915976

## Citation

> US National Institutes of Health, RePORTER application 9915976, Pathogenic mechanisms and therapeutics for the cardiac manifestations of myotonic dystrophy type 1 (5R01HL147020-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9915976. Licensed CC0.

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