Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.
Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.
复制标题
DOI：
10.1016/j.celrep.2015.11.028
复制
发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Berglund JA
中科院分区：
文献类型：
--
作者：
Siboni RB;Nakamori M;Wagner SD;Struck AJ;Coonrod LA;Harriott SA;Cass DM;Tanner MK;Berglund JA
肌强直性营养不良1型（DM1）是一种遗传性疾病，其特征是无法放松收缩的肌肉。受影响的个体携带大量的CTG扩增，当转录时是有毒的。一个可能的治疗方法是减少或消除CTG重复序列的转录。放线菌素D （ActD）是一种有效的转录抑制剂和fda批准的化疗药物，可以高亲和力地结合富含gc的DNA。在这里，我们报告了在DM1细胞和小鼠模型中，与作为一般转录抑制剂或化疗药物相比，在显著较低浓度（纳摩尔）下，ActD以剂量依赖的方式降低了CUG转录水平。在DM1小鼠模型中，ActD也显著逆转了DM1相关的剪接缺陷，并且在目前批准的人类治疗范围内也是如此。RNA-seq分析显示，在DM1小鼠模型中，低浓度的ActD没有全面抑制转录。这些结果表明，抑制CTG扩增是一种很有前途的治疗DM1的方法。
Myotonic Dystrophy type 1 (DM1) is an inherited disease characterized by the inability to relax contracted muscles. Affected individuals carry large CTG expansions that are toxic when transcribed. One possible treatment approach is to reduce or eliminate transcription of CTG repeats. Actinomycin D (ActD) is a potent transcription inhibitor and FDA-approved chemotherapeutic that binds GC-rich DNA with high affinity. Here, we report that ActD decreased CUG transcript levels in a dose-dependent manner in DM1 cell and mouse models at significantly lower concentrations (nanomolar) compared to its use as a general transcription inhibitor or chemotherapeutic. ActD also significantly reversed DM1-associated splicing defects in a DM1 mouse model, and did so within the currently approved human treatment range. RNA-seq analyses showed that low concentrations of ActD did not globally inhibit transcription in a DM1 mouse model. These results indicate that transcription inhibition of CTG expansions is a promising treatment approach for DM1.