Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene
Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin ge...
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Elsevier
2012-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116301068 |
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doaj-bef9514bacf54e2886ea174f3e8695342020-11-24T23:17:13ZengElsevierMolecular Therapy: Nucleic Acids2162-25312012-01-011C10.1038/mtna.2012.40Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin GeneSue Fletcher0Carl F. Adkin1Penny Meloni2Brenda Wong3Francesco Muntoni4Ryszard Kole5Clayton Fragall6Kane Greer7Russell Johnsen8Steve D. Wilton9Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaDepartment of Pediatrics, Cincinnati Children's Hospital Medical Centre and University of Cincinnati College of Medicine, Cincinnati, Ohio, USAThe Dubowitz Neuromuscular Centre, University College London, Institute of Child Health London, UKAVI Biopharma, Bothell, Washington, USASchool of Pathology and Laboratory Medicine, University of Western Australia, Perth, AustraliaCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, AustraliaProtein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear “leaky”, and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known “leaky” region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies.http://www.sciencedirect.com/science/article/pii/S2162253116301068antisense oligomersDuchenne muscular dystrophyexon skippingpersonalized genetic therapysplice-switching |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Sue Fletcher Carl F. Adkin Penny Meloni Brenda Wong Francesco Muntoni Ryszard Kole Clayton Fragall Kane Greer Russell Johnsen Steve D. Wilton |
| spellingShingle |
Sue Fletcher Carl F. Adkin Penny Meloni Brenda Wong Francesco Muntoni Ryszard Kole Clayton Fragall Kane Greer Russell Johnsen Steve D. Wilton Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene Molecular Therapy: Nucleic Acids antisense oligomers Duchenne muscular dystrophy exon skipping personalized genetic therapy splice-switching |
| author_facet |
Sue Fletcher Carl F. Adkin Penny Meloni Brenda Wong Francesco Muntoni Ryszard Kole Clayton Fragall Kane Greer Russell Johnsen Steve D. Wilton |
| author_sort |
Sue Fletcher |
| title |
Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene |
| title_short |
Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene |
| title_full |
Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene |
| title_fullStr |
Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene |
| title_full_unstemmed |
Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene |
| title_sort |
targeted exon skipping to address “leaky” mutations in the dystrophin gene |
| publisher |
Elsevier |
| series |
Molecular Therapy: Nucleic Acids |
| issn |
2162-2531 |
| publishDate |
2012-01-01 |
| description |
Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear “leaky”, and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known “leaky” region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies. |
| topic |
antisense oligomers Duchenne muscular dystrophy exon skipping personalized genetic therapy splice-switching |
| url |
http://www.sciencedirect.com/science/article/pii/S2162253116301068 |
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