Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy
<p>Abstract</p> <p>Background</p> <p>Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD). Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2007-07-01
|
| Series: | BMC Medical Genetics |
| Online Access: | http://www.biomedcentral.com/1471-2350/8/43 |
| _version_ | 1818864911231483904 |
|---|---|
| author | van Ommen Gert-Jan B Janson Anneke AM Aartsma-Rus Annemieke van Deutekom Judith CT |
| author_facet | van Ommen Gert-Jan B Janson Anneke AM Aartsma-Rus Annemieke van Deutekom Judith CT |
| author_sort | van Ommen Gert-Jan B |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD). Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple exon duplications. These mutations are in principle ideal targets for this approach since the specific skipping of duplicated exons would generate original, full-length transcripts.</p> <p>Methods</p> <p>Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed.</p> <p>Results</p> <p>For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62), by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons.</p> <p>Conclusion</p> <p>The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches.</p> |
| first_indexed | 2024-12-19T10:39:10Z |
| format | Article |
| id | doaj.art-0b9d8287a04a4b24b13ac23e081d3dc1 |
| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-19T10:39:10Z |
| publishDate | 2007-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genetics |
| spelling | doaj.art-0b9d8287a04a4b24b13ac23e081d3dc12022-12-21T20:25:30ZengBMCBMC Medical Genetics1471-23502007-07-01814310.1186/1471-2350-8-43Antisense-induced exon skipping for duplications in Duchenne muscular dystrophyvan Ommen Gert-Jan BJanson Anneke AMAartsma-Rus Annemiekevan Deutekom Judith CT<p>Abstract</p> <p>Background</p> <p>Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD). Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple exon duplications. These mutations are in principle ideal targets for this approach since the specific skipping of duplicated exons would generate original, full-length transcripts.</p> <p>Methods</p> <p>Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed.</p> <p>Results</p> <p>For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62), by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons.</p> <p>Conclusion</p> <p>The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches.</p>http://www.biomedcentral.com/1471-2350/8/43 |
| spellingShingle | van Ommen Gert-Jan B Janson Anneke AM Aartsma-Rus Annemieke van Deutekom Judith CT Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy BMC Medical Genetics |
| title | Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy |
| title_full | Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy |
| title_fullStr | Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy |
| title_full_unstemmed | Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy |
| title_short | Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy |
| title_sort | antisense induced exon skipping for duplications in duchenne muscular dystrophy |
| url | http://www.biomedcentral.com/1471-2350/8/43 |
| work_keys_str_mv | AT vanommengertjanb antisenseinducedexonskippingforduplicationsinduchennemusculardystrophy AT jansonannekeam antisenseinducedexonskippingforduplicationsinduchennemusculardystrophy AT aartsmarusannemieke antisenseinducedexonskippingforduplicationsinduchennemusculardystrophy AT vandeutekomjudithct antisenseinducedexonskippingforduplicationsinduchennemusculardystrophy |