# The role of TGFβs and cFAPs in Cardiac Pathology from RNA Toxicity

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $790,857

## 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 (CMR) 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
four independent but complementary aims. First, based on preliminary evidence of increased TGFβs expression
in the heart, we will determine the role of TGFβs from cardiomyocytes, in RNA toxicity in the heart. Second, we
will study the behavior of cardiac fibro-adipogenic progenitors (cFAP) cells and the role of TGFβ signaling in
cFAPs in pathologic responses to RNA toxicity. Third, we will study the therapeutic response to therapies
targeting TGFβs (isoform specific antibodies against TGFβ2 and TGFβ3). Fourth, we will evaluate next
generation ASOs that target the toxic RNA. With both these classes of therapy, we will assess their therapeutic
effect on fibroadipogenic changes, cFAPs, TGFβ expression and cardiac outcomes, by using ECGs and CMR
and functional testing. The ultimate goal of this proposal is to elucidate critical players in the primary pathologies
associated with RNA toxicity in the heart, and to identify pathways and therapies that may mitigate morbidity and
mortality associated with cardiac disease in DM1.

## Key facts

- **NIH application ID:** 10868516
- **Project number:** 5R01HL169790-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mani Subramaniam Mahadevan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $790,857
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868516

## Citation

> US National Institutes of Health, RePORTER application 10868516, The role of TGFβs and cFAPs in Cardiac Pathology from RNA Toxicity (5R01HL169790-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10868516. Licensed CC0.

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