This excerpt is from a Science Daily post on a recent article in the in the peer-reviewed journal Science Translational Medicine, "Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy." Click here to read more.
Drugs are currently being tested that show promise in treating patients with Duchenne muscular dystrophy (DMD), an inherited disease that affects about one in 3,600 boys and results in muscle degeneration and, eventually, death.
"Dantrolene is such an attractive candidate to test in this disease as it's already approved, has been used safely in humans for decades and we won't have to go through the lengthy and costly drug development process," Nelson said. "We were very pleased to find out that this drug seems to work synergistically with the drugs being tested now on boys with DMD."
DMD is caused by mutations in the Duchene gene, located on the X chromosome and necessary for correct muscle cell function. The mutations prohibit production of the protein dystrophin, causing the muscles, as well as the heart and respiratory system, to deteriorate. An exon or exons are deleted in the mutant gene, causing the cellular machinery to "skip over" the exon and making what was once a readable genetic instruction unreadable.
The drugs being tested in DMD boys now use small pieces of DNA called antisense oligonucleotides to act as molecular patches that allow for the production of dystrophin. The trials thus far have shown that the exon skipping therapy is working, however not enough dystrophin is being produced for fully normal muscle function. Nelson and Miceli sought out molecules that could give a boost to the exon skipping drugs so DMD patients can produce enough dystrophin for more normal muscle function.
Abstract 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.
Copyright © 2012, American Association for the Advancement of Science
Citation: G. C. Kendall, E. I. Mokhonova, M. Moran, N. E. Sejbuk, D. W. Wang, O. Silva, R. T. Wang, L. Martinez, Q. L. Lu, R. Damoiseaux, M. J. Spencer, S. F. Nelson, M. C. Miceli, Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy. Sci. Transl. Med. 4, 164ra160 (2012).
Sci Transl Med 12 December 2012: Vol. 4 no. 164 pp. 164ra160 DOI:10.1126/scitranslmed.3005054