Abstract
Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.
Highlights
The zebrafish Danio rerio has rapidly been adopted as an organism of choice for all aspects of the drug discovery pipeline [1,2,3]
Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy
The loss of other dystrophin glycoprotein complex (DGC) components in the absence of dystrophin is common with other models of Duchenne muscular dystrophy (DMD) such as the mdx mouse [21], and in people with DMD [22]
Summary
The zebrafish Danio rerio has rapidly been adopted as an organism of choice for all aspects of the drug discovery pipeline [1,2,3]. The zebrafish system offers unique advantages for drug screening in a vertebrate model organism, and in particular, muscular dystrophies are especially amenable due to their early, robust and readily recognizable phenotypes [4,5]. The small size, embryonic status, low cost and ease of drug delivery directly via the water, makes zebrafish a very attractive model for whole-organism screening. Of the genes known to be mutated in human forms of muscular dystrophy, many are represented in the zebrafish genome and those investigated so far exhibit dystrophic phenotypes in zebrafish [7,8]. Candidate compounds identified in fish would need to be validated in mammals before being taken on to human therapy, the low cost and speed of candidate drug screening, far outweigh any disadvantages
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