Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat
Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat
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DOI：
10.2119/molmed.2013.00011
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发表时间：
2013-01-01
影响因子：
5.7
通讯作者：
Saccone, Valentina
中科院分区：
文献类型：
--
作者：
Consalvi, Silvia;Mozzetta, Chiara;Saccone, Valentina
以前的工作已经证实，营养不良肌肉中存在组蛋白脱乙酰基酶(HDAC)信号通路--抗肌营养不良蛋白-一氧化氮(NO)。因此，针对HDAC(即HDAC抑制剂)的药物干预对于肌营养不良症的治疗具有潜在的治疗意义。在这项研究中，我们探讨了不同剂量的HDAC抑制剂吉维诺坦对Duchenne肌营养不良症(DMD)小鼠模型MDX小鼠的长期治疗效果。这项研究确定了在5到10 mg/kg/d的吉维诺斯特的窗口内恢复功能和组织学参数的有效性，而1 mg/kg/d的有益影响明显减少。长期(3.5个月)暴露于1.5个月龄的MDX小鼠中，最佳浓度的吉维诺坦促进了横截面积增加的肌肉的形成，减少了纤维化疤痕和脂肪渗透，导致跑步机测试中耐力能力的全面改善和膜的稳定性增加。有趣的是，暴露于5 mg/kg/d和10 mg/kg/d吉维诺斯特的MDX小鼠肌肉中的炎性浸润物减少。一项平行的药代动力学/药效学分析证实了吉维诺斯特的有效剂量与药物在治疗小鼠肌肉和血液中的分布之间的关系。这些发现为吉维诺斯特立即转化为对DMD患者的临床研究提供了临床前基础。
Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice-the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.