Identifying FDA-Approved Drugs that Upregulate Utrophin A as a Therapeutic Strategy for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations and deletions within the DMD gene, which result in a lack of dystrophin protein at the sarcolemma of skeletal muscle fibers. The absence of dystrophin fragilizes the sarcolemma and compromises its integrity during cycles of muscle contraction, which, progressively, leads to reductions in muscle mass and function. DMD is thus a progressive muscle-wasting disease that results in a loss of ambulation, cardiomyopathy , respiratory impairment, and death. Although there is presently no cure for DMD, recent advances have led to many promising treatments. One such approach entails increasing expression of a homologous protein to dystrophin, named utrophin A, which is endogenously expressed in both healthy and DMD muscle fibers. Upregulation of utrophin A all along the sarcolemma of DMD muscle fibers can, in part, compensate for the absence of dystrophin. Over the years, our laboratory has focused a significant portion of our efforts in identifying and characterizing drugs and small molecules for their ability to target utrophin A and cause its overexpression. As part of these efforts, we have recently developed a novel ELISA-based high-throughput drug screen, to identify FDA-approved drugs that increase the expression of utrophin A in muscle cells in culture as well as in dystrophic mice. Here, we describe our overall strategy to identify and characterize several FDA-approved drugs that upregulate utrophin A expression and provide details on all experimental approaches. Such strategy has the potential to lead to the rapid development of novel therapeutics for DMD.