Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides

@article{Wilton1999SpecificRO,
  title={Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides},
  author={Steve D. Wilton and Frances Lloyd and Kylie S. Carville and Sue Fletcher and Kaite Honeyman and Sudhir Agrawal and Ryszard Kole},
  journal={Neuromuscular Disorders},
  year={1999},
  volume={9},
  pages={330-338}
}
The mdx mouse, which carries a nonsense mutation in exon 23 of the dystrophin gene, has been used as an animal model of Duchenne muscular dystrophy to evaluate cell or gene replacement therapies. Despite the mdx mutation, which should preclude the synthesis of a functional dystrophin protein, rare, naturally occurring dystrophin-positive fibres have been observed in mdx muscle tissue. These dystrophin-positive fibres are thought to have arisen from an exon-skipping mechanism, either somatic… Expand
Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse.
  • C. Mann, K. Honeyman, +6 authors S. Wilton
  • Medicine, Biology
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2001
TLDR
This approach should reduce the severity of DMD by allowing a dystrophic gene transcript to be modified, such that it can be translated into a Becker-dystrophin-like protein. Expand
Induction of revertant fibres in the mdx mouse using antisense oligonucleotides
TLDR
This work demonstrates the feasibility of AO cocktails to by-pass dystrophin mutation hotspots through multi-exon skipping, so that the same AO formulations may be applied to several different mutations within particular domains of the dyStrophin gene. Expand
Restoration of dystrophin expression in mdx muscle cells by chimeraplast-mediated exon skipping.
TLDR
Data demonstrate that chimeraplasts can induce exon skipping by altering splice site sequences at the genomic level, which has the potential to be used to transform a severe DMD phenotype into a much milder BMD phenotype. Expand
Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle.
TLDR
Data is presented showing that exon skipping in mdx cells may be induced by morpholino AOs at nanomolar concentrations when annealed to a sense oligonucleotide or "leash", and delivered as a cationic lipoplex. Expand
Redirecting splicing to address dystrophin mutations: molecular by-pass surgery.
TLDR
From interesting in vitro experiments several years ago, the dystrophin exon-skipping field has progressed to the stage of planning for clinical trials, which may be regarded as a form of by-pass surgery at the molecular level. Expand
Personalised genetic intervention for Duchenne muscular dystrophy: antisense oligomers and exon skipping.
TLDR
The view of regulatory authorities in assessing preclinical data on potentially scores of different but class-specific compounds will be of paramount importance in expediting the clinical application of exon skipping therapy for this serious and relentlessly progressive muscle wasting disease. Expand
Screening for antisense modulation of dystrophin pre-mRNA splicing
TLDR
The results of an optimisation of splicomer sequence design by the use of both high-throughput arrays and biological screens have resulted in specific and, importantly, exclusive skipping of the targeted exon in greater than 60% of dystrophin mRNA, leading to the de novo synthesis and localisation of dyStrophin protein in cultured mdx muscle cells. Expand
The influence of antisense oligonucleotide length on dystrophin exon skipping.
TLDR
Data from in vitro studies in murine and human cells is presented showing that appropriately designed AOs of 25-31 nucleotides are generally more effective at inducing exon skipping than shorter counterparts, however, there appears to be an upper limit in optimal length. Expand
Treatment of Duchenne Muscular Dystrophy with Oligonucleotides against an Exonic Splicing Enhancer Sequence
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease and so far, the treatment of DMD has not yet been established. We have proposed a novel treatment for DMD whereby theExpand
Effective exon skipping and restoration of dystrophin expression by peptide nucleic acid antisense oligonucleotides in mdx mice.
  • H. Yin, Q. Lu, M. Wood
  • Biology, Medicine
  • Molecular therapy : the journal of the American Society of Gene Therapy
  • 2008
TLDR
It is demonstrated that PNAs have a higher efficiency of exon skipping than 2'O methyl phosphorothioate AOs do, and have a potential use in AO chemistry for antisense therapy of DMD. Expand
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References

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TLDR
A novel approach to correct dystrophin deficiency at the post-transcriptional level by transfection of muscle cells with antisense RNA, which may in the future offer a therapeutic approach for DMD, as well as for other inherited disorders. Expand
Dystrophin gene transcripts skipping the mdx mutation
TLDR
A sensitive nested polymerase chain reaction‐based examination of dystrophin gene transcripts around the mdx mutation has revealed several alternatively processed transcripts that skipped the mutation in exon 23, were in‐frame, and could be translated into a shorter but still functional dystophin protein. Expand
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TLDR
It is predicted that specific loss of the brain promoter may be one cause of X chromosome-linked mental retardation in patients with Duchenne muscular dystrophy. Expand
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TLDR
Using in situ hybridisation with antisense oligonucleotides, expression of four distinct mRNAs in specific brain areas is demonstrated and reveals a new complexity to dystrophin expression that may have important insights for mental retardation mechanisms. Expand
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TLDR
Results showed that antisense ODN against ERS can induce exon skipping even in living cells and ERS is functioning as an essential cis-element for proper splicing in dystrophin pre-mRNA. Expand
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TLDR
The mdx mouse has a myopathy caused by dystrophin deficiency, and is therefore biochemically and genetically homologous to human Duchenne muscular dystrophy and a possible estimate of the somatic reversion rate of the mdx mutation in vivo is considered. Expand
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TLDR
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TLDR
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TLDR
Treatment of mammalian cells stably expressing the IVS2-654 human beta-globin gene with antisense oligonucleotides targeted at the aberrant splice sites restored correct splicing in a dose-dependent fashion, generating correct human Beta- globin mRNA and polypeptide. Expand
Immunohistological evidence for second or somatic mutations as the underlying cause of dystrophin expression by isolated fibres in Xp21 muscular dystrophy of Duchenne-type severity
TLDR
Using five monoclonal antibodies against different parts of the dystrophin molecule, it is interpreted as the first in situ evidence of an individual having different patterns of missing exons leading to restoration of the reading frame in various ways in the original germline frame-shifting deletion of exons 35-43. Expand
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