Résumé :
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Myostatin and Transforming Growth Factor (TGF)-beta play important roles in regulation of muscle differentiation and fibrosis, and are emerging as attractive therapeutic targets in the treatment of Duchenne Muscular Dystrophy (DMD). We specifically targeted myostatin/TGF-beta type 1 receptors Acvr1b (Alk4) and Tgfbr1 (Alk5) using antisense oligoribonucleotides (AON) against regions in the pre-mRNA encoding ligand binding and/or kinase domains of the receptors. Transfection of Acvr1b or Tgfbr1 AONs to C2C12 cells results in skipping of the targeted exon, ~50% downregulation of the full length transcript and enhanced myoblast differentiation. In addition, local administration into the skeletal muscles of mdx mice provokes considerable downregulation of full length Acvr1b (~80%) or Tgfbr1 (~50%), leading to ~50% increase in expression of myogenin and ~40 % decrease in expression of fibrotic markers. We used the Acvr1b and Tgfbr1 AONs to study how TGF-beta and myostatin signaling are regulated in different cell types. Myostatin exclusively uses the Acvr1b receptor for signaling in myoblasts, while myostatin shows preference for Tgfbr1 in nonmuscle cells. Moreover, we demonstrate the potential of dual exon skipping strategies for DMD, simultaneously targeting the primary cause by skipping in Dmd, and the secondary consequences by skipping in Acvr1b and/or Tgfbr1. Systemic administrations are currently ongoing to further assess the therapeutic benefits of these AONs and to determine the differential effect of Acvr1b and Tgfbr1 knockdown on the dystrophic pathology of the mdx mice.
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