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Lu-Nguyen N, Malerba A, Popplewell L, et al. Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice. Mol Ther Nucleic Acids. 2016;6:15-28doi: 10.1016/j.omtn.2016.11.009.
Lu-Nguyen, N., Malerba, A., Popplewell, L., Schnell, F., Hanson, G., & Dickson, G. (2017). Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice. Molecular therapy. Nucleic acids, 615-28. https://doi.org/10.1016/j.omtn.2016.11.009
Lu-Nguyen, Ngoc, et al. "Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice." Molecular therapy. Nucleic acids vol. 6 (2017): 15-28. doi: https://doi.org/10.1016/j.omtn.2016.11.009
Lu-Nguyen N, Malerba A, Popplewell L, Schnell F, Hanson G, Dickson G. Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice. Mol Ther Nucleic Acids. 2017 Mar 17;6:15-28. doi: 10.1016/j.omtn.2016.11.009. Epub 2016 Dec 10. PMID: 28325281; PMCID: PMC5363451.
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Mol Ther Nucleic Acids. 2017 Mar 17;6:15-28. doi: 10.1016/j.omtn.2016.11.009. Epub 2016 Dec 10.

Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice.

Molecular therapy. Nucleic acids

Ngoc Lu-Nguyen, Alberto Malerba, Linda Popplewell, Fred Schnell, Gunnar Hanson, George Dickson

Affiliations

  1. School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
  2. Sarepta Therapeutics Inc., 215 First Street, Cambridge, MA 02142, USA.
  3. School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK. Electronic address: [email protected].

PMID: 28325281 PMCID: PMC5363451 DOI: 10.1016/j.omtn.2016.11.009

Abstract

Antisense-mediated exon skipping is a promising approach for the treatment of Duchenne muscular dystrophy (DMD), a rare life-threatening genetic disease due to dystrophin deficiency. Such an approach can restore the disrupted reading frame of dystrophin pre-mRNA, generating a truncated form of the protein. Alternatively, antisense therapy can be used to induce destructive exon skipping of myostatin pre-mRNA, knocking down myostatin expression to enhance muscle strength and reduce fibrosis. We have reported previously that intramuscular or intraperitoneal antisense administration inducing dual exon skipping of dystrophin and myostatin pre-mRNAs was beneficial in mdx mice, a mouse model of DMD, although therapeutic effects were muscle type restricted, possibly due to the delivery routes used. Here, following systemic intravascular antisense treatment, muscle strength and body activity of treated adult mdx mice increased to the levels of healthy controls. Importantly, hallmarks of muscular dystrophy were greatly improved in mice receiving the combined exon-skipping therapy, as compared to those receiving dystrophin antisense therapy alone. Our results support the translation of antisense therapy for dystrophin restoration and myostatin inhibition into the clinical setting for DMD.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Duchenne muscular dystrophy; antisense oligonucleotides; dystrophin; exon skipping; myostatin

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