Targeting Cardiac Calcium Regulation and Fibrosis in DMD Models

  • Jeong, Dongtak (PI)

Project Details


Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene. In males with DMD-associated dilated cardiomyopathy, heart problems usually develop early in life and worsen quickly, leading to heart failure in adolescence or early adulthood. In affected females, the condition appears later in life and symptoms are gradual. Until recently, the major cause of death for 80%-90% of DMD patients was due to respiratory failure. However, with improvements in respiratory care, death due to cardiac-related diseases has become much more frequent. In fact, fibrosis of the heart is the second leading cause of death in DMD, occurring in more than 96% of DMD patients. Fibrotic lesions cause irregular heartbeats in addition to general structural stiffness, compromising the hearts ability to pump blood. Additionally, in dilated cardiomyopathy, heart muscle is enlarged and weakened, preventing the heart from pumping blood. This has become more frequent, occurring in up to 40% of patients. Signs and symptoms of this condition can include an irregular heartbeat (arrhythmia), shortness of breath, extreme tiredness (fatigue), and swelling of the legs and feet.

This Fiscal Year 2017 Duchenne Muscular Dystrophy Research Focus Area is Cardiac Studies, proposing to apply potential therapeutic interventions for DMD-caused dysfunction and fibrosis. The Principal Investigator's career goals are to apply highly potential gene therapy vectors, specifically miRNA-25 inhibition vectors, to improve cardiac contractility and decrease potential fibrosis that may occur. This award will advance his career in Duchenne research by allowing him to study the effect of the inhibition of miRNA-25 on key calcium regulation and fibrosis in the setting of DMD. In addition to the cellular mechanisms, overall functional effects will also be studied.

Ultimately, this research will help older DMD patients, a growing subpopulation due to improved respiratory care, who are suffering from cardiac dysfunction and fibrosis that affect patient's quality of life. Clinically, there is potential for gene therapy by inhibiting a microRNA-25 using tissue-specific viral vectors and transcription factors to improve cardiac regulation. Furthermore, by using a single microRNA to improve both cardiac contractility and decrease potential fibrosis, symptoms due to cardiac issues will be decreased. Although novel mechanisms of gene editing such as CRISPR has emerged, the potential side effects still need further studies. However, gene editing systems using viral vectors currently have been used clinically. Although it may take a few decades for clinical use, these preclinical trials will be essential to understand potential improvements as well as side effects of the vector.

Effective start/end date1/01/17 → …


  • Congressionally Directed Medical Research Programs: $434,102.00


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