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Long-Term Rescue of Dystrophin Expression and Improvement in Muscle Pathology and Function in Dystrophic Mdx Mice by Peptide-Conjugated Morpholino

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https://ir.library.oregonstate.edu/concern/articles/wd375x04j

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  • Exon skipping is capable of correcting frame-shift and nonsense mutations of Duchenne Muscular Dystrophy (DMD). Phase II clinical trials in UK and Netherlands have reported induction of dystrophin expression in muscles of DMD patients by systemic administrations of both phosphorodiamidate morpholino oligomers (PMO) and 2’O methyl phosphorothioate. Peptide-conjugated PMO (PPMO) offers significantly higher efficiency than PMO with the ability to induce near normal levels of dystrophin and restores functions in both skeletal and cardiac muscles. Here, we examined one year systemic efficacy of PPMO targeting exon 23 in dystrophic mdx mice. LD50 of the PPMO was approximately 85mg/kg. Half life of the dystrophin expression was about 2 months in skeletal muscles but shorter in cardiac muscle. Biweekly injection of 6 mg/kg PPMO produced higher than 20% dystrophin expression in all skeletal muscles, and up to 5% in cardiac muscles with improvement in muscle function and pathology, and reduction in the levels of serum creatine kinase (CK). Monthly injections of 30mg/kg PPMO restored dystrophin to more than 50% normal levels in all of skeletal muscles, but 15% in cardiac muscle. This was associated with greatly reduced serum CK levels, near normal histology, and functional improvement of skeletal muscles. Our result demonstrated for the first time that one year regular administration of PPMO could be safely applied to achieve significant therapeutic effect in animal models.
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  • Wu, B., Lu, P., Cloer, C., Shaban, M., Grewal, S., Milazi, S., . . . Lu, Q. (2012). Long-term rescue of dystrophin expression and improvement in muscle pathology and function in dystrophic mdx mice by peptide-conjugated morpholino. American Journal of Pathology, 181(2), 392-400. doi: 10.1016/j.ajpath.2012.04.006
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  • 181
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  • 2
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  • This work was supported by the Carolinas Muscular Dystrophy Research Endowment at the Carolinas HealthCare Foundation and Carolinas Medical Center, Charlotte, NC, NIH, MA USA and by U.S. Army Medical Research, Department of Defense (W81XWH-05-1-0616, W81XWH-09-1-0599.).
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