Fast Skeletal Muscle Myosin Inhibitors Confer Protection to mdx Mice Receiving Glucocorticoid Steroid Treatment


Pre-Clinical Research

Poster Number: 134


Angela Peter, PhD, Edgewise Therapeutics, Ying Qian, BS, Edgewise Therapeutics, Breanne Newell-Stamper, PhD, Edgewise Therapeutics, Steven Schlachter, BS, Edgewise Therapeutics, Carlos del Rio, PhD, Edgewise Therapeutics, Marc Evanchik, MS, Edgewise Therapeutics, Alan Russell, PhD, Edgewise Therapeutics

Dystrophin-deficient muscle is characterized by progressive muscle atrophy and weakness due to repeated cycles of injury and incomplete regeneration. Glucocorticoid (GC) steroid treatments, namely deflazacort and prednisone, have been shown both pre-clinically and clinically to slow this progression in dystrophin-deficient muscle and are commonly prescribed to Duchenne muscular dystrophy (DMD) patients. We hypothesize that sarcomere-stabilization of susceptible dystrophin-deficient fast-twitch muscle fibers, via selective myosin-inhibition, can blunt injury upstream of the inflammatory and membrane leakage processes, thus providing myo-protective effects in DMD even in the setting of GC treatment. We tested this hypothesis by evaluating the effects of a novel fast skeletal myosin inhibitor in muscle function and membrane stability in mdx mice receiving deflazacort. In this study, groups of mdx mice (8 weeks old) received daily treatments with deflazacort (0.3mg/kg or 1.2 mg/kg) and/or a novel selective fast skeletal myosin inhibitor (EDG) for 3 weeks. At the end of the study, forelimb grip strength and membrane stability, as determined by lower-body Evan’s Blue Dye (EBD) uptake, were assessed. EDG-treated group showed enhanced membrane stabilization (reduced EBD leakage) when compared to animals receiving deflazacort alone; all animal receiving EDG showed blunted EBD-uptake, suggesting deflazacort-independent membrane stabilization. In summary, sarcomere stabilization via a novel fast-skeletal selective myosin-inhibitor provided muscle protection, blunting membrane permeability, in dystrophin-deficient animals when administered concomitantly with standard-of-care glucocorticoid treatment. Thus, myosin-stabilization may offer long-term benefits for DMD patients, regardless of the background therapy.