PUBLICATION
Evaluation of Exon-Skipping Strategies for Duchenne Muscular Dystrophy Utilizing Dystrophin-deficient Zebrafish
- Authors
- Berger, J., Berger, S., Jacoby, A.S., Wilton, S.D., and Currie, P.D.
- ID
- ZDB-PUB-110124-17
- Date
- 2011
- Source
- Journal of Cellular and Molecular Medicine 15(12): 2643-51 (Journal)
- Registered Authors
- Berger, Joachim, Berger, Silke, Currie, Peter D., Jacoby, Arie
- Keywords
- Dystrophin, DMD, Duchenne Muscular Dystrophy, zebrafish, muscle, exon-skipping
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Dystrophin/physiology*
- Exons/genetics*
- Humans
- Muscular Dystrophy, Duchenne/genetics*
- Phenotype
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Zebrafish/genetics*
- Zebrafish/growth & development
- Zebrafish/metabolism
- PubMed
- 21251213 Full text @ J. Cell. Mol. Med.
Citation
Berger, J., Berger, S., Jacoby, A.S., Wilton, S.D., and Currie, P.D. (2011) Evaluation of Exon-Skipping Strategies for Duchenne Muscular Dystrophy Utilizing Dystrophin-deficient Zebrafish. Journal of Cellular and Molecular Medicine. 15(12):2643-51.
Abstract
Duchenne Muscular Dystrophy is a severe muscle wasting disease caused by mutations in the dystrophin gene. By utilising antisense oligonucleotides, splicing of the dystrophin transcript can be altered so that exons harbouring a mutation are excluded from the mature mRNA. While this approach has been shown to be effective to restore partially functional dystrophin protein, the level of dystrophin protein that is necessary to rescue a severe muscle pathology has not been addressed. As zebrafish dystrophin mutants (dmd) resemble the severe muscle pathology of human patients, we have utilised this model to evaluate exon-skipping. Novel dmd mutations were identified to enable the design of phenotype rescue studies via morpholino administration. Correlation of induced exon-skipping efficiency and the level of phenotype rescue suggests that relatively robust levels of exon-skipping are required to achieve significant therapeutic ameliorations and that pre-screening analysis of exon-skipping drugs in zebrafish may help to more accurately predict clinical trials for therapies of Duchenne Muscular Dystrophy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping