Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice
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 p...
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doaj-fb5b3e81c93e42398ea04b7f262f473e2020-11-25T02:13:24ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-03-0161528Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx MiceNgoc Lu-Nguyen0Alberto Malerba1Linda Popplewell2Fred Schnell3Gunnar Hanson4George Dickson5School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UKSchool of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UKSchool of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UKSarepta Therapeutics Inc., 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics Inc., 215 First Street, Cambridge, MA 02142, USASchool of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK; Corresponding author: George Dickson, School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.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. Keywords: antisense oligonucleotides, Duchenne muscular dystrophy, dystrophin, exon skipping, myostatinhttp://www.sciencedirect.com/science/article/pii/S2162253116303675 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ngoc Lu-Nguyen Alberto Malerba Linda Popplewell Fred Schnell Gunnar Hanson George Dickson |
spellingShingle |
Ngoc Lu-Nguyen Alberto Malerba Linda Popplewell Fred Schnell Gunnar Hanson George Dickson Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice Molecular Therapy: Nucleic Acids |
author_facet |
Ngoc Lu-Nguyen Alberto Malerba Linda Popplewell Fred Schnell Gunnar Hanson George Dickson |
author_sort |
Ngoc Lu-Nguyen |
title |
Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice |
title_short |
Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice |
title_full |
Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice |
title_fullStr |
Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice |
title_full_unstemmed |
Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice |
title_sort |
systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice |
publisher |
Elsevier |
series |
Molecular Therapy: Nucleic Acids |
issn |
2162-2531 |
publishDate |
2017-03-01 |
description |
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. Keywords: antisense oligonucleotides, Duchenne muscular dystrophy, dystrophin, exon skipping, myostatin |
url |
http://www.sciencedirect.com/science/article/pii/S2162253116303675 |
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