Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse.
Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse.
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DOI：
10.1016/j.omtn.2018.02.002
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Miceli MC
中科院分区：
文献类型：
--
作者：
Wang DW;Mokhonova EI;Kendall GC;Becerra D;Naeini YB;Cantor RM;Spencer MJ;Nelson SF;Miceli MC
Duchenne肌营养不良症(DMD)是由DMD的突变引起的，导致对肌肉健康至关重要的肌营养不良蛋白的丢失。DMD“外显子跳过”利用反义寡核苷酸(AON)在mRNA加工过程中强制特定的外显子排除，以恢复阅读框架和挽救部分功能的Dstrophin蛋白。尽管在人类身上跳过外显子的药物显示出希望，但被拯救的dystrophin蛋白水平仍然不是最理想的。我们之前在人类DMD培养和短期MDX营养不良小鼠研究中发现丹曲林与Aon联合使用时是一种跳跃增强剂。在这里，我们评估了丹曲林/Aon联合治疗在更接近潜在人体剂量的条件下跳过长期MDX治疗的DMD外显子-23的效果。为了评估丹曲林/Aon联合治疗对dystrophin诱导的效果，我们测试了口服丹曲林和不口服丹曲林的三种Aon剂量，以评估不同肌肉的多重结果。对来自股四头肌和横隔肌的统计测试结果的荟萃分析，评估了丹曲林对Aon以外的所有Aon治疗组的贡献，提供了强有力的证据，表明丹曲林适度促进了mdx鼠的外显子跳跃和dystrophin救援，同时减少了mdx鼠的肌肉病理(p<；0.0087)。这些发现支持Dantrolene/Aon的联合试验，以提高跳过外显子的疗效，并强调组合方法和食品和药物管理局(FDA)药物再利用的价值，以发现意外的治疗应用和快速翻译。
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.
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影响因子：
17.1
作者：
Biressi S;Miyabara EH;Gopinath SD;Carlig PM;Rando TA
通讯作者：
Rando TA
影响因子：
3.5
作者：
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作者：
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通讯作者：
Tewari, Muneesh