Wang Derek W, Mokhonova Ekaterina I, Kendall Genevieve C, Becerra Diana, Naeini Yalda B, Cantor Rita M, Spencer Melissa J, Nelson Stanley F, Miceli M Carrie
Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine and College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine and College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Mol Ther Nucleic Acids. 2018 Jun 1;11:180-191. doi: 10.1016/j.omtn.2018.02.002. Epub 2018 Feb 13.
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD "exon skipping" uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies. Here, we assess the effect of dantrolene/AON combination on DMD exon-23 skipping over long-term mdx treatment under conditions that better approximate potential human dosing. To evaluate the dantrolene/AON combination treatment effect on dystrophin induction, we assayed three AON doses, with and without oral dantrolene, to assess multiple outcomes across different muscles. Meta-analyses of the results of statistical tests from both the quadriceps and diaphragm assessing contributions of dantrolene beyond AON, across all AON treatment groups, provide strong evidence that dantrolene modestly boosts exon skipping and dystrophin rescue while reducing muscle pathology in mdx mice (p < 0.0087). These findings support a trial of combination dantrolene/AON to increase exon-skipping efficacy and highlight the value of combinatorial approaches and Food and Drug Administration (FDA) drug re-purposing for discovery of unsuspected therapeutic application and rapid translation.
杜兴氏肌营养不良症（DMD）由DMD基因突变引起，导致肌营养不良蛋白缺失，而肌营养不良蛋白对肌肉健康至关重要。DMD“外显子跳跃”利用反义寡核苷酸（AON）在mRNA加工过程中强制特定外显子排除，以恢复阅读框并挽救部分功能性肌营养不良蛋白。尽管人类的外显子跳跃药物显示出前景，但挽救的肌营养不良蛋白水平仍不理想。我们之前在人类DMD培养物和短期mdx营养不良小鼠研究中发现，丹曲林与AON联合使用时可作为跳跃增强剂。在此，我们在更接近潜在人类给药的条件下，评估丹曲林/AON组合对长期mdx治疗中DMD外显子23跳跃的影响。为了评估丹曲林/AON联合治疗对肌营养不良蛋白诱导的效果，我们测定了三种AON剂量，分别加用和不加用口服丹曲林，以评估不同肌肉的多种结果。对来自股四头肌和膈肌的统计测试结果进行荟萃分析，评估所有AON治疗组中丹曲林在AON之外的作用，结果提供了有力证据，表明丹曲林适度促进外显子跳跃和肌营养不良蛋白挽救，同时减少mdx小鼠的肌肉病理改变（p < 0.0087）。这些发现支持对丹曲林/AON联合用药进行试验，以提高外显子跳跃疗效，并突出了组合方法以及美国食品药品监督管理局（FDA）药物重新利用在发现意外治疗应用和快速转化方面的价值。
