Targeting Cardiac Calcium Regulation and Fibrosis in DMD Models
Abstract
Cardiomyopathy is a prominent feature of Duchenne Muscular Dystrophy (DMD) with increased intracellular Ca2+ and significant interstitial fibrosis being major pathophysiological hallmarks. miRNA-25 has been identified as a suppressor of both SERCA2a and Smad7 in several experimental animal models. In Phase I, we united miR-25 TuD with AAV9, in order to assess the effect of miR-25 inhibition on cardiac function in aged dystrophin/utrophin (MDX/UTRN) KO mice which is a validated transgenic murine model for DMD. We found that AAV9 miR-25 TuD transfer resulted in the strong and stable inhibition of cardiac miR-25 levels. This resulted in increased SERCA2a and Smad7 expression and in turn improved cardiac function, decreased cardiac fibrosis, and also lead to a significantly improved survival rate. In Phase II, we generated new AAV vectors with various promoters to obtain tissue specific expression and minimize off-target effect. Conclusively, we could achieve a better tissue specificity using these promoters but there is clear imitation using current AAV constructs in terms of the intensity of target gene expression, which should be addressed in further studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2020
- Accession Number
- AD1115242
Entities
People
- Jeong Dongtak
Organizations
- Icahn School of Medicine at Mount Sinai