# RNA Toxicity and Cardiac Pathology

> **NIH NIH R56** · UNIVERSITY OF VIRGINIA · 2022 · $754,977

## Abstract

Project Summary:
Myotonic dystrophy (DM1), the most common form of muscular dystrophy in adults and children, is an autosomal
dominant genetic disorder caused by an expanded CTG repeat in the DM protein kinase (DMPK) gene that leads
to nuclear retention of the mutant RNA and subsequent RNA toxicity. The heart is one of the primary organs
affected in DM1. Cardiac conduction problems are present in up to 75% of adult DM1 cases, and sudden death
due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis
of cardiac manifestations in DM1 is not well understood. Clinical focus for cardiac disease in DM1 has been on
arrhythmias and conduction abnormalities. Of note, the pathology of cardiac defects in DM1 has been historically
associated with interstitial fibrosis, and fatty infiltration and fibrosis of cardiac conduction tissues. We reported
the first inducible mouse model of RNA toxicity and cardiac conduction defects and demonstrated the potential
for reversibility of DM1 phenotypes by silencing toxic RNA production. Recently using the DM200 mouse model,
we showed for the first time, the potential for antisense oligonucleotides (ASOs) to treat cardiac disease in DM1.
We also found evidence for fibrotic changes associated with RNA toxicity in the heart. In the past decade, the
advent of new cardiac MRI studies has led to evidence of and an increased interest in understanding cardiac
fibrosis in DM1 and its role in the clinical pathology of DM1. We propose to use the DM200 mouse model as a
tool for developing and investigating these ideas and concepts in a pre-clinical model and to try to understand
the cellular and molecular drivers of fibro-adipogenic changes in the heart. We will do this through three
independent but complementary aims. First, we will develop and evaluate cardiac MRI as a biomarker for RNA
toxicity in the heart. Second, we will determine the role of cardiac PDGFRA+ve cells in fibro/adipogenic
pathologic responses to RNA toxicity in the heart. Third, based on preliminary evidence of increased TGFβ in
the heart, we will characterize the role of TGFβs in RNA toxicity in the heart, and study the therapeutic response
to therapies targeting fibrosis and TGFβ (including isoform specific antibodies against TGFβ2 and TGFβ3).
Importantly, we will validate the CMR protocols and parameters in therapeutic trials using: a) next generation
ASOs that target the toxic RNA and b) the therapies targeting fibrosis and TGFβs. Our goals are to understand
the drivers of cardiac pathology associated with RNA toxicity in DM1, and to evaluate and establish the potential
utility of cardiac MRI as a tool to monitor disease progression and response to therapy.

## Key facts

- **NIH application ID:** 10705364
- **Project number:** 1R56HL162953-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mani Subramaniam Mahadevan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $754,977
- **Award type:** 1
- **Project period:** 2022-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705364

## Citation

> US National Institutes of Health, RePORTER application 10705364, RNA Toxicity and Cardiac Pathology (1R56HL162953-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10705364. Licensed CC0.

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