# Activity and therapeutic antagonism of the TP receptor in cardiomyopathy of muscular dystrophy

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $688,125

## Abstract

PROJECT SUMMARY
Duchenne muscular dystrophy (DMD) is characterized by membrane instability, calcium influx, and necrosis of
myocytes. In the heart, progressive breakdown of cardiomyocytes causes fibrosis and an insidious dilated
cardiomyopathy. Heart failure is the primary cause of death in patients with DMD, which occurs around the
third decade despite traditional cardiosupportive therapeutics. Our preliminary research suggests that signaling
from the thromboxane-prostanoid receptor (TPr) in the heart is a driving force leading to cardiomyocyte death
and fibrosis, and preventing this activity may preserve cardiac function in muscular dystrophy patients. Our
group has found that blocking TPr activity with the antagonist ifetroban improves survival, cardiac function, and
cardiac fibrosis in two mouse models of severe DMD and a model of limb-girdle muscular dystrophy. Based on
these studies, a Phase 2 clinical study of ifetroban in DMD patients is currently recruiting. However, key
knowledge gaps exist. We know that TPr activation leads to fibrosis with enhanced tumor growth factor (TGF)-
β activity, but not how it activates TGFβ. Here we will test the hypothesis that TPr activation mediates TGF-β
release from the large latent complex, leading to cardiac fibrosis. We will test this in the context of TPr
blockade or deletion, using mdx/utrn(+/-) mice or mdx mice containing latent TGF-β binding protein-4 (LTBP4)
polymorphism, and confirm with isolated fibroblasts. Our early data also suggests that the mechanism by which
TPr regulates cardiomyocyte membrane stability, arrhythmia, and cardiac function may be distinct from this.
We hypothesize this occurs via regulation of calcium influx and calcium-activated signaling, and that
antagonism improves this in mdx/utrn(+/-) mice in a manner additive with standard-of-care therapies. A DMD
mouse model containing a cardiomyocyte-specific deletion of TPr will separate cardiomyocyte-initiated from
fibroblast effects. Finally, our ongoing trial presents a unique opportunity to assess molecular outcomes
longitudinally in human patients, and identify biomarkers to reflect the cardiac response to TPr antagonism. For
this aim, we will do expression profiling of peripheral blood mononuclear cells from DMD patient participants in
the ifetroban clinical trial, compared with response to treatment. Resolving these questions will illuminate the
role of the TPr in DMD cardiomyopathy, anticipate human response and mechanism of TPr antagonism in
DMD patients, and could provide valuable surrogate endpoints for drug response.

## Key facts

- **NIH application ID:** 10872165
- **Project number:** 5R01HL167110-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JAMES D WEST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $688,125
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872165

## Citation

> US National Institutes of Health, RePORTER application 10872165, Activity and therapeutic antagonism of the TP receptor in cardiomyopathy of muscular dystrophy (5R01HL167110-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10872165. Licensed CC0.

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