Dasatinib as a treatment for Duchenne muscular dystrophy

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.

A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies

“…Zebrafish motion-tracking platforms and analyses of swimming behaviors are a powerful tool to determine the overall locomotive capabilities in a given time frame under nonstimulatory conditions (25). Previously, these platforms have been able to show significant decreases in overall larval motility in dystrophin-deficient (sapje) zebrafish when compared with sibling controls (26). We next tested the overall locomotion of the fkrp -/zebrafish at 5 dpf as compared with wild-type and heterozygous sibling control fish using the DanioVision locomotive tracking platform.…”

Retrograde trafficking of β-dystroglycan from the plasma membrane to the nucleus

“…The phosphorylation of β-DG on Tyr 892 16 , 17 prevents its interaction with utrophin or dystrophin 33 , 34 , and is a stimulus for its endocytic uptake and subsequent localization to early endosomes. Thus, it would be predicted that the nuclear localization of β-DG is positively modulated by this post-translational modification.…”

γ‐Secretase Dependent Nuclear Targeting of Dystroglycan

“…Additional modifications to β‐dystroglycan, however, are phosphorylation on tyrosine [James et al, ; Sotgia et al, ], and specific proteolytic cleavage events [Losasso et al, ; Singh et al, ; Mitchell et al, ]. Tyrosine phosphorylation of β‐dystroglycan serves as a molecular switch to regulate the binding of different cellular binding partners [Moore and Winder, ], but is also a signal for the internalization of dystroglycan from the plasma membrane [Miller et al, ; Lipscomb et al, ], and may mediate some proteolytic events and nuclear translocation [Mathew et al, ; Mitchell et al, ]. β‐dystroglycan is subject to proteolysis at several key sites: matrix metalloproteinase‐mediated cleavage liberates the extracellular portion of β‐dystroglycan [Yamada et al, ; Zhong et al, ], the extracellular portion is not detectable as no antibody reagent to it exists, but the remaining 31 kDa transmembrane stub and cytoplasmic domain can be detected with antibodies to the carboxy‐terminus of the cytoplasmic domain.…”