The dystrophin gene mutations found in Duchenne muscular dystrophy (DMD) contribute to progressive weakness and failure of skeletal and cardiac muscles. Steroid treatment and advances in respiratory therapy have increased the life expectancy for DMD by 10 years; however, these patients now succumb to complications associated with cardiomyopathy in their late twenties and early thirties. Currently, there is no cure or selective treatment for the ultimately fatal dystrophin-deficient cardiomyopathy. The mechanisms underlying dystrophin- deficient cardiomyopathy are not fully established, but significant amounts of data indicate that oxidative stress, altered calcium signaling, and mitochondrial damage contribute to dystrophin-deficient cardiomyocyte malfunction and death. Using human DMD induced pluripotent stem cell derived cardiomyocytes, and the muscular dystrophy (mdx) mouse model, we have shown that the pharmaceutical nicorandil protects against dystrophin-deficiency in the heart and cardiomyocyte. Nicorandil also modulates the levels of microRNAs secreted from the DMD-cardiomyocytes encapsulated in extracellular vesicles. Here we are further developing nicorandil as a therapeutic to treat DMD cardiomyopathy and to develop miR-related biomarkers to monitor therapeutic efficacy. We will test whether nicorandil protects against the development of cardiomyopathy in the muscular dystrophy mouse, modulates miR levels in secreted extracellular vesicles, and whether nicorandil- responsive miRs modulate reactive oxygen species formation, calcium cycling, and mitochondrial function in dystrophin-deficient cardiomyocytes. Results from these studies will be clinically relevant and may impact the development of new treatments for this devastating disease.

Public Health Relevance

Duchenne Muscular Dystrophy is the most common lethal genetic disorder of childhood. The proposed research will develop the pharmaceutical nicorandil and companion biomarkers for the treatment of DMD cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134932-02
Application #
9416836
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Burns, Kristin
Project Start
2017-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226