New Approach for Antisense Oligonucleotide-Mediated Exon Skipping in Duchenne Muscular Dystrophy
Yoshitsugu Aoki, Tetsuya Nagata, and Shin’ichi Takeda
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan
Duchenne Muscular Dystrophy (DMD) is a lethalmuscle disorder characterized by mutations in the DMD gene. These mutations primarily disrupt the reading frame, resulting in the absence of functional dystrophin protein. Exon skipping, which involves the use of antisense oligonucleotides is a promising therapeutic approach for DMD, and clinical trials on exon skipping are currently underway in DMD patients. Recently, stable and less-toxic antisense oligonucleotides with higher efficacy have been developed in mouse and dog models of DMD. This review highlights a new approach for antisense oligonucleotide-based therapeutics for DMD, particularly for exon skipping-based methods.
-  E. P. Hoffman et al., “Dystrophin: the protein product of the Duchenne muscular dystrophy locus,” Cell, Vol.51, pp. 919-928, 1987.
-  E. Ozawa et al., “Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era,” Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., Vol.86, pp. 798-821, 2010.
-  A. P. Monaco et al., “An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus,” Genomics, Vol.2, pp. 90-95, 1988.
-  Y. Aoki et al., “Antisense Oligonucleotide-Mediated Exon 51-Skipping Therapy for Duchenne Muscular Dystrophy,” Int. J. of Advanced Computer Science, Vol.1, pp. 209-214, 2011.
-  M. Ruth et al., “Replicating GM Viruses in Cancer Therapy;A Conflict of Emotions,” J. of Disaster Research, Vol.6, pp. 514-520, 2011.
-  Q. L. Lu et al., “Massive idiosyncratic exon skipping corrects the nonsense mutation in dystrophic mouse muscle and produces functional revertant fibers by clonal expansion,” J. Cell Bio., Vol.148, pp. 985-996, 2000.
-  A. Nakamura et al., “Exon-skipping therapy for Duchenne muscular dystrophy,” Lancet, Vol.378, pp. 546-547, 2011.
-  M. Matsuo et al., “Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe,” J. Clin. Invest., Vol.87, pp. 2127-2131, 1991.
-  M. Koenig et al., “The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion,” Am. J. Hum. Genet., Vol.45, pp. 498-506, 1989.
-  A. Aartsma-Rus et al., “Theoretic applicability of antisensemediated exon skipping for Duchenne muscular dystrophy mutations,” Hum. Mutat., Vol.30, pp. 293-299, 2009.
-  F. Muntoni et al., “Targeting RNA to treat neuromuscular disease,” Nat. Rev. Drug Discov., Vol.10, pp. 621-637, 2011.
-  MG. Dunckley et al., “Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides,” Hum. Mol. Genet., Vol.7, pp. 1083-1090, 1998.
-  T. Saito et al., “Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient,” PLoS One, Vol.5, e12239, 2010.
-  J. Alter et al., “Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology,” Nat. Med., Vol.12, pp. 175-177, 2006.
-  T. Yokota et al., “Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs,” Ann. Neurol., Vol.65, pp. 667-676, 2009.
-  Y. Aoki et al., “In-frame Dystrophin Following Exon 51-Skipping Improves Muscle Pathology and Function in the Exon 52-Deficient mdx Mouse,” Mol. Ther., Vol.18, pp. 1995-2005, 2010.
-  E. Araki et al., “Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy,” Biochem. Biophys. Res. Commun., Vol.238, pp. 492-497, 1997.
-  J. C. van Deutekom et al., “Local dystrophin restoration with antisense oligonucleotide PRO051,” N. Engl. J. Med., Vol.357, pp. 2677-2686, 2007.
-  M. Kinali et al., “Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-ofconcept study,” Lancet. Neurol., Vol.8, pp. 918-928, 2009.
-  NM. Goemans et al., “Systemic administration of PRO051 in Duchenne’s muscular dystrophy,” N. Eng. J. Med., Vol.364, pp. 1513-1522, 2011.
-  S. Cirak et al., “Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study,” Lancet, Vol.378, pp. 595-605, 2011.
-  B. Wu et al., “Dose-dependent restoration of dystrophin expression in cardiac muscle of dystrophic mice by systemically delivered morpholino,” Gene. Ther., Vol.17, pp. 132-140, 2010.
-  M. Taniguchi-Ikeda et al., “Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy,” Nature, Vol.478, pp. 127-131, 2011.
This article is published under a Creative Commons Attribution-NoDerivatives 4.0 Internationa License.