Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice
| Autor: | Ngoc Lu-Nguyen, Amer F. Saleh, George Dickson, Linda Popplewell, Michael J. Gait, Susan Jarmin |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Reading Frames Duchenne muscular dystrophy Myostatin Morpholinos Muscle hypertrophy Dystrophin Mice Exon Drug Discovery biology Exons musculoskeletal system Molecular Medicine Original Article medicine.symptom musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty government.form_of_government Diaphragm Arginine Necrosis Open Reading Frames Internal medicine Genetics medicine Animals Muscle Skeletal Molecular Biology Pharmacology Antisense therapy Muscle weakness Genetic Therapy Oligonucleotides Antisense medicine.disease Molecular biology Exon skipping Mice Inbred C57BL Muscular Dystrophy Duchenne Alternative Splicing Disease Models Animal Endocrinology Animals Newborn Mice Inbred mdx biology.protein government Peptides |
| Zdroj: | Molecular Therapy. 23:1341-1348 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2015.88 |
| Popis: | The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD. |
| Databáze: | OpenAIRE |
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