Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
EMBO Mol Med. 2013 Oct;5(10):1569-85. doi: 10.1002/emmm.201302621. Epub 2013 Sep 9.
Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.
肌营养不良蛋白的缺失使骨骼肌更容易受到损伤，导致杜氏肌营养不良症（DMD）的细胞膜破裂和慢性炎症。目前使用糖皮质激素治疗的效果不明确，且副作用较大。目前尚不清楚是否有避免激素对生长发育的抑制和/或免疫抑制的治疗方法会更有益或更无益。在这里，我们发现了一种口服药物，其作用机制通过抗炎信号和膜稳定途径提供疗效，而不依赖于激素或免疫抑制作用。我们发现 VBP15 可以保护和促进激光损伤后的骨骼肌细胞的有效修复，与泼尼松龙相反。NF-κB 的强力抑制是通过糖皮质激素受体的蛋白相互作用介导的，然而 VBP15 显示出明显降低的激素受体转录活性。这些药物机制在 DMD 模型小鼠中的转化通过预防和发病后干预方案改善了肌肉力量、活体成像和病理学。这些数据表明，VBP15 可以成功改善营养不良症，而不依赖于激素、生长或免疫抑制作用，这表明 VBP15 值得对 DMD 进行临床研究，并且将有益于其他慢性炎症性疾病。
