Project 434747

Duchenne Muscular Dystrophy (DMD) is a fatal genetic disease caused by mutations in dystrophin, the largest gene in humans. This gene produces a protein called dystrophin, which is critical to maintain long term structure and function of muscle fibers. Loss of dystrophin leads to the development of very weak muscle fibers, which cannot sustain the forces of contraction, leading to loss of muscle function and and death in early adulthood. Over the preceding two decades the investigation of new treatment options for DMD has primarily focused on two objectives. The foremost effort has focused on replacing the defective dystrophin gene, while other strategies have been developed to protect or reduce DMD muscle fiber fragility. However, recent investigations suggest that dystrophic muscle also suffers from an inherent loss in muscle regeneration capacity. Specifically, DMD muscle stem cells are incapable of initiating the maturation process and the production of new muscle fibers. In this proposal, we highlight our efforts to identify mechanisms that can be used to over-ride this stem cell defect in DMD and promote robust production of new muscle fibers. We have identified a protein that is critical to this process (caspase 3) and we propose to test a new drug/small molecule that stimulates this factor to engage stem cell maturation in DMD muscle. We anticipate that our studies will provide a first in class therapeutic to improve muscle regeneration and reduce DMD disease progression.