Grant: Project Grant

Duchenne muscular dystrophy is a disease of muscle that affects approximately 1 in 3500 live male births. Disease starts early in life when young boys fail to reach key milestones in their motor development and it is progressive; children are soon bound to a wheelchair and most die in their 20s and 30s from cardiac and respiratory complications. At present there is no cure for DMD. The underlying genetic cause of DMD is well-known; patients carry a mutation in the dystrophin gene. Muscle cells fail to make dystrophin protein and muscle tissues are not stable. Lack of dystrophin leads to a breakdown of the Dystrophin Glycoprotein Complex (DGC) protein complex and consequently results in muscle membrane fragility, damage, inflammation, and cell death. Recent technical developments in the areas of stem-cell therapy and gene editing have given renewed hope to developing a treatment for DMD. However, we have identified a knowledge gap in our understanding of the effects of DMD mutations on the physiology of human muscle and synapses. Our proposed experiments are designed to fill this gap and will subsequently direct our studies of therapeutic treatments, especially research into repurposing existing pharmaceuticals while developing new therapies. To enable this research, we have developed a pioneering 3D muscle cell culture system to analyze the neuromuscular physiology and structure of human muscle cells grown from healthy and DMD-patient stem cells. These human muscle neuro-muscular microtissues will serve as the model system in our studies. By completing this work we will derive new knowledge into the effects of DMD mutations on human neuro-muscular physiology while in parallel testing the therapeutic efficacy of compounds directed towards improving the performance of DMD-affected muscle.