In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse.
A promising therapeutic approach for Duchenne muscular dystrophy (DMD) is exon skipping using antisense oligonucleotides (AOs). In-frame deletions of the hinge 3 region of the dystrophin protein, which is encoded by exons 50 and 51, are predicted to cause a variety of phenotypes. Here, we performed...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2010
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| _version_ | 1797066152471429120 |
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| author | Aoki, Y Nakamura, A Yokota, T Saito, T Okazawa, H Nagata, T Takeda, S |
| author_facet | Aoki, Y Nakamura, A Yokota, T Saito, T Okazawa, H Nagata, T Takeda, S |
| author_sort | Aoki, Y |
| collection | OXFORD |
| description | A promising therapeutic approach for Duchenne muscular dystrophy (DMD) is exon skipping using antisense oligonucleotides (AOs). In-frame deletions of the hinge 3 region of the dystrophin protein, which is encoded by exons 50 and 51, are predicted to cause a variety of phenotypes. Here, we performed functional analyses of muscle in the exon 52-deleted mdx (mdx52) mouse, to predict the function of in-frame dystrophin following exon 51-skipping, which leads to a protein lacking most of hinge 3. A series of AOs based on phosphorodiamidate morpholino oligomers was screened by intramuscular injection into mdx52 mice. The highest splicing efficiency was generated by a two-oligonucleotide cocktail targeting both the 5' and 3' splice sites of exon 51. After a dose-escalation study, we systemically delivered this cocktail into mdx52 mice seven times at weekly intervals. This induced 20-30% of wild-type (WT) dystrophin expression levels in all muscles, and was accompanied by amelioration of the dystrophic pathology and improvement of skeletal muscle function. Because the structure of the restored in-frame dystrophin resembles human dystrophin following exon 51-skipping, our results are encouraging for the ongoing clinical trials for DMD. Moreover, the therapeutic dose required can provide a suggestion of the theoretical equivalent dose for humans. |
| first_indexed | 2024-03-06T21:38:19Z |
| format | Journal article |
| id | oxford-uuid:47081d5d-853e-435e-b51f-001777287eb1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:38:19Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:47081d5d-853e-435e-b51f-001777287eb12022-03-26T15:17:30ZIn-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:47081d5d-853e-435e-b51f-001777287eb1EnglishSymplectic Elements at Oxford2010Aoki, YNakamura, AYokota, TSaito, TOkazawa, HNagata, TTakeda, SA promising therapeutic approach for Duchenne muscular dystrophy (DMD) is exon skipping using antisense oligonucleotides (AOs). In-frame deletions of the hinge 3 region of the dystrophin protein, which is encoded by exons 50 and 51, are predicted to cause a variety of phenotypes. Here, we performed functional analyses of muscle in the exon 52-deleted mdx (mdx52) mouse, to predict the function of in-frame dystrophin following exon 51-skipping, which leads to a protein lacking most of hinge 3. A series of AOs based on phosphorodiamidate morpholino oligomers was screened by intramuscular injection into mdx52 mice. The highest splicing efficiency was generated by a two-oligonucleotide cocktail targeting both the 5' and 3' splice sites of exon 51. After a dose-escalation study, we systemically delivered this cocktail into mdx52 mice seven times at weekly intervals. This induced 20-30% of wild-type (WT) dystrophin expression levels in all muscles, and was accompanied by amelioration of the dystrophic pathology and improvement of skeletal muscle function. Because the structure of the restored in-frame dystrophin resembles human dystrophin following exon 51-skipping, our results are encouraging for the ongoing clinical trials for DMD. Moreover, the therapeutic dose required can provide a suggestion of the theoretical equivalent dose for humans. |
| spellingShingle | Aoki, Y Nakamura, A Yokota, T Saito, T Okazawa, H Nagata, T Takeda, S In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title_full | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title_fullStr | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title_full_unstemmed | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title_short | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. |
| title_sort | in frame dystrophin following exon 51 skipping improves muscle pathology and function in the exon 52 deficient mdx mouse |
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