# Project 2

> **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $548,811

## Abstract

Project Summary/Abstract for Project 2
Duchenne muscular dystrophy (DMD) is a recessive X-linked neuromuscular disorder resulting from mutations
in the dystrophin gene, which ultimately produces progressive muscle wasting and atrophy. Importantly, DMD
patients develop cardiac fibrosis and a decrease in cardiac function leading to advanced cardiomyopathy,
which is currently the major contributor to mortality in DMD patients. The mission of the UT Southwestern
Wellstone Center is to develop CRISPR/Cas9 genome editing as a therapeutic modality for DMD patients;
however, issues related to DMD-associated cardiomyopathy will continue to persist. Project 1 proposes to use
genome editing to target the 12 “hot spots” within the dystrophin gene making a truncated dystrophin protein
and converting a DMD patient into a Becker muscular dystrophy (BMD) patient. Thus, the overall goal of
Project 2 is to develop novel therapies to attenuate the morbidity and mortality associated with DMD-
associated cardiomyopathy. Significant strides have been made in treating non-DMD cardiomyopathy;
however, there are no definitive therapies to effectively induce long term reverse cardiac remodeling and
improve overall cardiac function within DMD patients. Our group has undertaken a cardiac MRI study
demonstrating that adult DMD patients have very low left ventricular (LV) mass as well as low LV concentricity
as compared to age-, sex-, and weight-matched control patients. Once a DMD patient develops symptoms
related to advanced cardiomyopathy, the DMD heart starts to dilate and enlarge resembling the structure of
advanced dilated non-ischemic cardiomyopathy. These observations raise the question whether the
development of pathological cardiac hypertrophy is the primary mechanism underlying DMD-associated
cardiomyopathy. Does the observed low LV mass and concentricity arise due to prolonged immobility or are
independent of a DMD patient’s ability to ambulate? Data from the Mammen Laboratory indicates that mdx
mice, a murine model of DMD, have altered cardiac metabolism and also have low cardiac mass due to a
decrease in proliferative gene expression during the first week of life. Therefore, the central hypothesis of
Project 2 is that low LV mass and concentricity in DMD-associated cardiomyopathy leads to progressive
cardiomyopathy independent of a DMD patient’s ability to ambulate. To test our central hypothesis, we will
pursue the following three specific aims: Specific Aim 1: Characterize the clinical and molecular phenotypes
in ambulatory and non-ambulatory DMD patients as a function of patient age. Specific Aim 2: Define the
cardiac phenotype in BMD-associated cardiomyopathy as a function of patient age and site of the genetic
mutation. Specific Aim 3: Determine the molecular phenotypes of human DMD and BMD cardiomyocytes.

## Key facts

- **NIH application ID:** 10049129
- **Project number:** 2P50HD087351-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** PRADEEP P.A. MAMMEN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $548,811
- **Award type:** 2
- **Project period:** 2015-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049129

## Citation

> US National Institutes of Health, RePORTER application 10049129, Project 2 (2P50HD087351-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049129. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*