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Human Molecular Genetics:达沙替尼(dasatinib)有望治疗DMD

来源:wendong 2016-01-08 09:18

在最近的一项研究中,谢菲尔德大学(University of Sheffield)研究人员发现,一种通常用于治疗白血病的药物表现出延缓杜氏肌营养不良(DMD)病情发展的潜力。

研究人员研究了一种名为达沙替尼(dasatinib)的药物,该药物通过阻断某些刺激癌细胞生长的化学信号来发挥作用。他们发现,该药物也会关闭一种与DMD有牵连的蛋白质中的类似信号。这种蛋白质被称为dystroglycan,在维护肌肉组织健康中发挥部分作用。

研究人员在DMD斑马鱼模型中测试了该药物,并且记录了40%的疾病改善。与对照组相比,达沙替尼治疗的斑马鱼游得更远,时间更长。通过将该药物和其他目前正在开发的疗法相结合,它们的疗效可能进一步提高。研究结果发表于《Human Molecular Genetics》期刊。

"达沙替尼确实有望作为DMD疗法"领导这项研究的Steve Winder教授说,"基于对该药物工作机制的理解,我们相信它可能有效延缓肌肉退化,延长患者的行走能力,并保护他们的心脏和呼吸肌肉。存在一种可能,如果患者获得诊断后立即服用该药,疾病发展可能会大幅减少。"

由于达沙替尼已经在临床使用,研究人员希望能更快地将其作为DMD疗法进行人体试验。在小鼠中的实验已经开始,并获得不错的效果。Winder教授的团队也在研究其他工作方式与达沙替尼类似的药物。

肌营养不良英国研究主任Marita Pohlschmidt博士说:"这些是关于DMD独特新疗法路径的令人鼓舞的结果。DMD是一种复杂的疾病,我们认为有效的治疗将需要组合疗法。Winder教授的方法可能补充目前正在推进通过临床试验的潜在疗法,使它们更有效。"

"我们希望能够适时地针对其他肌肉营养不良来研究该药物的治疗潜力。目前,我们期待在DMD的进一步研究中获得结果以支持这些早期发现。"(生物谷 Bioon.com)

DOI: 10.1093/hmg/ddv469

Dasatinib as a treatment for Duchenne muscular dystrophy

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.

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