PUBLICATION
Drug screening in a zebrafish model of Duchenne muscular dystrophy
- Authors
- Kawahara, G., Karpf, J.A., Myers, J.A., Alexander, M.S., Guyon, J.R., and Kunkel, L.M.
- ID
- ZDB-PUB-110328-7
- Date
- 2011
- Source
- Proceedings of the National Academy of Sciences of the United States of America 108(13): 5331-6 (Journal)
- Registered Authors
- Guyon, Jeff, Kawahara, Genri, Kunkel, Louis M.
- Keywords
- phosphodiesterase inhibitor, chemical treatment
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Disease Models, Animal
- Drug Evaluation, Preclinical*
- Dystrophin/genetics*
- Dystrophin/metabolism
- Humans
- Muscular Dystrophy, Duchenne/drug therapy*
- Muscular Dystrophy, Duchenne/pathology
- Muscular Dystrophy, Duchenne/physiopathology*
- Oligonucleotides, Antisense
- Pharmaceutical Preparations*
- Phenotype
- Small Molecule Libraries
- Zebrafish/genetics*
- Zebrafish/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 21402949 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Kawahara, G., Karpf, J.A., Myers, J.A., Alexander, M.S., Guyon, J.R., and Kunkel, L.M. (2011) Drug screening in a zebrafish model of Duchenne muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America. 108(13):5331-6.
Abstract
Two known zebrafish dystrophin mutants, sapje and sapje-like (sap(c/100)), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping