Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.
Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.
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DOI：
10.1016/j.omtn.2017.05.007
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发表时间：
2017-06-16
期刊：
影响因子：
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通讯作者：
Puymirat J
中科院分区：
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作者：
Jauvin D;Chrétien J;Pandey SK;Martineau L;Revillod L;Bassez G;Lachon A;MacLeod AR;Gourdon G;Wheeler TM;Thornton CA;Bennett CF;Puymirat J
强直性肌营养不良1型(DM1)是一种遗传性肌营养不良症，由人肌营养不良症蛋白激酶(DMPK)基因3‘端非编码区(CTG)n三核苷酸重复序列异常扩增引起。其结果是，含有扩展的CUG重复序列的突变转录本保留在核焦点中，并改变了MBNL和CELF家族剪接调节因子的功能，导致受影响的DM1组织中特定转录本的选择性剪接错误调节。在本研究中，我们用针对DMPK基因3‘非编码区的2’-4‘限制性乙基修饰(ISIS 486178)反义寡核苷酸系统地治疗DMSXL小鼠，这导致不同骨骼肌中CUGexp RNA的丰度和焦点减少了70%，心脏减少了30%。此外，使用ISIS 486178 ASO治疗可以改善体重、肌肉力量和肌肉组织学，但没有检测到明显的毒性。这一证据表明，CUGexp RNA的减少改善了DM1患者的肌肉力量，表明在消除有毒RNA后，DM1患者的肌肉无力可能会得到改善。
Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG)n trinucleotide repeat in the 3′ UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2′-4′-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3′ UTR of the DMPK gene, which led to a 70% reduction in CUGexp RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart. Furthermore, treatment with ISIS 486178 ASO improved body weight, muscle strength, and muscle histology, whereas no overt toxicity was detected. This is evidence that the reduction of CUGexp RNA improves muscle strength in DM1, suggesting that muscle weakness in DM1 patients may be improved following elimination of toxic RNAs.