Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy

Susan A. M. Mulders; Walther J. A. A. van den Broek; Thurman M. Wheeler; Huib J. E. Croes; Petra van Kuik-Romeijn; Sjef J. de Kimpe; Denis Furling; Gerard J. Platenburg; Genevieve Gourdon; Charles A. Thornton; Be Wieringa; Derick G. Wansink

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Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy

机译：三重重复寡核苷酸介导的肌强直性营养不良中RNA毒性逆转。

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摘要

Myotonic dystrophy type 1 (DM1) is caused by toxicity of an expanded, noncoding (CUG)n tract in DM protein kinase (DMPK) transcripts. According to current evidence the long (CUG)n segment is involved in entrapment of muscleblind (Mbnl) proteins in ribonuclear aggregates and stabilized expression of CUG binding protein 1 (CUGBP1), causing aberrant premRNA splicing and associated patho-genesis in DM1 patients. Here, we report on the use of antisense oligonucleotides (AONs) in a therapeutic strategy for reversal of RNA-gain-of-function toxicity. Using a previously undescribed mouse DM1 myoblast-myotube cell model and DM1 patient cells as screening tools, we have identified a fully 2'-0-methyl-phosphorothioate-modified (CAG)7 AON that silences mutant DMPK RNA expression and reduces the number of ribonuclear aggregates in a selective and (CUG)n-length-dependent manner. Direct administration of this AON in muscle of DM1 mouse models in vivo caused a significant reduction in the level of toxic (CUG)n RNA and a normalizing effect on aberrant premRNA splicing. Our data demonstrate proof of principle for therapeutic use of simple sequence AONs in DM1 and potentially other unstable microsatellite diseases.

机译：1型肌强直性营养不良（DM1）是由DM蛋白激酶（DMPK）转录本中扩展的非编码（CUG）n道的毒性引起的。根据目前的证据，长（CUG）n片段参与了核盲聚集体中肌盲（Mbnl）蛋白的包埋和CUG结合蛋白1（CUGBP1）的稳定表达，从而导致DM1患者异常的premRNA剪接和相关的发病机制。在这里，我们报告了反义寡核苷酸（AONs）在逆转RNA增益功能毒性的治疗策略中的使用。使用以前未描述的小鼠DM1成肌细胞-成肌细胞模型和DM1患者细胞作为筛选工具，我们已经鉴定出完全2'-0-甲基硫代磷酸酯修饰的（CAG）7 AON，该突变体使突变DMPK RNA表达沉默并减少了核糖核以选择性和（CUG）n长度依赖性的方式聚集。在体内在DM1小鼠模型的肌肉中直接施用该AON会导致毒性（CUG）n RNA的水平显着降低，并对异常的premRNA剪接产生正常化作用。我们的数据证明了简单序列AON在DM1和潜在的其他不稳定微卫星疾病中的治疗性使用的原理证明。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2009年第33期|13915-13920|共6页
作者
Susan A. M. Mulders; Walther J. A. A. van den Broek; Thurman M. Wheeler; Huib J. E. Croes; Petra van Kuik-Romeijn; Sjef J. de Kimpe; Denis Furling; Gerard J. Platenburg; Genevieve Gourdon; Charles A. Thornton; Be Wieringa; Derick G. Wansink;
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作者单位

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;

Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642;

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;

Prosensa B.V., Leiden, The Netherlands;

Prosensa B.V., Leiden, The Netherlands;

Universite Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale (INSERM), UMRS 974, Institut de Myologie, 75013 Paris, France;

Prosensa B.V., Leiden, The Netherlands;

INSERM U781, Hopital Necker-Enfants Malades, 75015 Paris, France;

Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642;

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Cell Biology (code 283), NCMLS, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
antisense oligonucleotide; microsatellite; muscle; pathogenesis; RNA silencing;

机译：反义寡核苷酸微卫星肌肉;发病;RNA沉默;

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专利

1. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . deLorimier Elaine, Coonrod Leslie A., Copperman Jeremy, Nucleic Acids Research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
2. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . Alex Taber, Elaine deLorimier, Emily E. Reister, Nucleic acids research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
3. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . Alex Taber, Elaine deLorimier, Emily E. Reister, Nucleic acids research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
4. Diagnosis of Myotonic Dystrophy Based on Resting State fMRI Using Convolutional Neural Networks [C] . Tahereh Kamali, Katharine A. Hagerman, John W. Day, Annual International Conference of the IEEE Engineering in Medicine and Biology Society . 2020

机译：基于卷积神经网络的静止状态功能磁共振成像对强直性肌营养不良的诊断
5. CCUG repeat toxicity in myotonic dystrophy type 2 (DM2). [D] . Margolis, Jamie Marie. 2008

机译：CCUG对2型强直性肌营养不良症（DM2）重复毒性。
6. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy [O] . Susan A. M. Mulders, Walther J. A. A. van den Broek, Thurman M. Wheeler, 2009

机译：三重重复寡核苷酸介导的肌强直性营养不良中RNA毒性逆转。
7. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy [O] . Mulders, Susan A. M., van den Broek, Walther J. A. A., Wheeler, Thurman M., 2009

机译：三重重复寡核苷酸介导的肌强直性营养不良中RNA毒性逆转。

Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy

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