Dantrolene aumenta o salto de exon em modelo humano e murino de distrofia muscular
USA – dantrole é uma droga usada no tratamento da hipertermia maligna; aplicado por via intramuscular ou venosa em camundongos com distrofia muscular, em conjunto com oligonucleotídeos, a droga causou uma maior quantidade de salto de exons do que o tratamento isolado com oligonucleotídeos. O uso do dantrole em cultura de células resultou em efeito semelhante.
(Sci Transl Med 12 December 2012: Vol. 4, Issue 164, p. 164ra160) Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy
Genevieve C. Kendall, Ekaterina I. Mokhonova, 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, and M. Carrie Miceli -USA
Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness and loss, resulting in early death. DMD is usually caused by frameshifting deletions in the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds to F-actin and components of the dystrophin-associated glycoprotein complex and protects the sarcolemma from contraction-induced injury. Antisense oligonucleotide–mediated exon skipping is a promising therapeutic approach aimed at restoring the DMD reading frame and allowing expression of an intact dystrophin glycoprotein complex. To date, low levels of dystrophin protein have been produced in humans by this method. We performed a small-molecule screen to identify existing drugs that enhance antisense-directed exon skipping. We found that dantrolene, currently used to treat malignant hyperthermia, potentiates antisense oligomer–guided exon skipping to increase exon skipping to restore the mRNA reading frame, the sarcolemmal dystrophin protein, and the dystrophin glycoprotein complex in skeletal muscles of mdx mice when delivered intramuscularly or intravenously. Further, dantrolene synergized with multiple weekly injections of antisense to increase muscle strength and reduce serum creatine kinase in mdx mice. Dantrolene similarly promoted antisense-mediated exon skipping in reprogrammed myotubes from DMD patients. Ryanodine and Rycal S107, which, like dantrolene, targets the ryanodine receptor, also promoted antisense-driven exon skipping, implicating the ryanodine receptor as the critical molecular target.
