Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy

• DOI: 10.1126/scitranslmed.3005054
• Publication Date: 2012-12-12T19:22:16Z
• Authors: Genevieve C. Kendall; Ekaterina I. Mokh...; Miriana Moran; Natalia E. Sejbuk; Derek W. Wang; Oscar Silva; Richard T. Wang; Leonel Martinez; Qi L. Lu; Robert Damoiseaux; Melissa J. Spencer; Stanley F. Nelson; M. Carrie Miceli
• Keywords: Exon skipping; mdx mouse; Morpholino; Sarcolemma

Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness loss, resulting in early death. DMD is usually caused by frameshifting deletions the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds F-actin components dystrophin-associated glycoprotein complex protects sarcolemma from contraction-induced injury. Antisense oligonucleotide-mediated exon skipping a promising therapeutic approach aimed at restoring reading frame allowing expression an intact complex. To date, low levels protein have been produced humans this method. We performed small-molecule screen identify existing drugs that enhance antisense-directed skipping. found dantrolene, currently used treat malignant hyperthermia, potentiates antisense oligomer-guided increase restore mRNA frame, sarcolemmal protein, skeletal muscles mdx mice when delivered intramuscularly or intravenously. Further, dantrolene synergized with multiple weekly injections strength reduce serum creatine kinase mice. Dantrolene similarly promoted antisense-mediated reprogrammed myotubes patients. Ryanodine Rycal S107, which, like targets ryanodine receptor, also antisense-driven skipping, implicating receptor as critical molecular target.