Grant: Operating Grant - E-Rare-2 Joint Transnational Call on Rare Diseases

Duchenne Muscular Dystrophy (DMD) is a rare and devastating genetic disease of childhood manifested by progressive debilitating skeletal muscle weakness and wasting, and ultimately death. The Rudnicki group recently identified a role for Wnt7a/Fzd7 signaling in stimulating the regeneration of muscle by acting at two levels. Wnt7a acts on satellite stem cells to drive their symmetric expansion, and also acts on myofibers to stimulate hypertrophy. Delivery of Wnt7a significantly ameliorated dystrophic changes in the mdx mouse model of DMD. The research team represents an outstanding multidisciplinary group of investigators, who are uniquely positioned to conduct the proposed basic and preclinical studies. The overall goal of the project is to assess the utility of Wnt7a and its variants as protein therapeutics for the stimulation of intrinsic regeneration for the treatment of DMD. We propose to characterize the Wnt7a/Fzd7 signaling pathway at the molecular level and identify downstream target genes to elucidate mode of action. We will characterize the long-term effects of intramuscular injection of Wnt7a protein on muscle intergrity and strength in dystrophin-deficient mdx mice. We will globally express Wnt7a in skeletal muscle using a MLC1-Wnt7a transgene. We will investigate the basis for the suppression of the inflammatory response by Wnt7a. Finally, we will assess the activity of Wnt7a on human satellite cells and myofibers in mice carrying humanized DMD muscle. These experiments will advance our knowledge of Wnt7a signaling in muscle and illuminate the therapeutic potential of Wnt7a as a protein biologic to stimulate intrinsic repair in a muscle-wasting disease like DMD. Furthermore, the information generated by the proposed studies will inform the preclinical development of Wnt7a towards undertaking a first Phase I clinical trial.