Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy.
Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy.
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Antagomir-218的临床前表征是肌营养不良症的潜在治疗方法。
DOI：
10.1016/j.omtn.2021.07.017
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Artero R
中科院分区：
文献类型：
--
作者：
Cerro-Herreros E;González-Martínez I;Moreno N;Espinosa-Espinosa J;Fernández-Costa JM;Colom-Rodrigo A;Overby SJ;Seoane-Miraz D;Poyatos-García J;Vilchez JJ;López de Munain A;Varela MA;Wood MJ;Pérez-Alonso M;Llamusí B;Artero R
强直性肌营养不良1型（DM 1）是一种罕见的神经肌肉疾病，由DMPK基因非编码区不稳定CTG重复序列扩增引起。突变体DMPK转录物中的CUG扩增在核糖核灶中隔离MBNL 1蛋白。这种蛋白质的消耗是疾病症状如肌无力和萎缩以及肌强直的主要贡献者，然而内源性MBNL 1水平的上调可以补偿这种隔离。先前已经证明针对miR-218的反义寡核苷酸在疾病模型中促进MBNL 1表达并拯救表型，在此我们使用HSALR小鼠模型和患者来源的肌管提供了miR-218分子的临床前表征。在HSALR中，注射后2周，EscheromiR-218达到40-60 pM，以剂量和时间依赖性方式挽救分子和功能表型，并在单次皮下给药后显示出良好的毒性特征。在肌肉组织中，EscheromiR挽救了Mbnl 1的正常亚细胞分布，并且没有改变含有CUG病灶的肌核的比例。在患者来源的细胞中，EkomiR-218改善了融合和分化缺陷，并挽救了患者细胞转录组中高达34%的基因表达改变。重要的是，发现miR-218在DM 1肌肉活检中上调，将这种microRNA（miRNA）确定为相关的治疗靶点。增强MBNL 1表达水平是寻求开发神经肌肉疾病强直性肌营养不良的有效疗法的治疗选择。Arabian及其同事发现，其翻译阻遏物miR-218在疾病样本中过表达，并报告了成肌细胞转录组和由miR-218抑制的miR-218所带来的体内拯救。
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40–60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target. Enhancing MBNL1 expression levels is a therapeutic option in the quest to develop effective therapies for the neuromuscular disease myotonic dystrophy. Artero and colleagues found that its translational repressor, miR-218, is overexpressed in disease samples and report myoblast transcriptome and in vivo rescues brought about by antagomiRs against miR-218.
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影响因子：
4.6
作者：
Chen G;Masuda A;Konishi H;Ohkawara B;Ito M;Kinoshita M;Kiyama H;Matsuura T;Ohno K
通讯作者：
Ohno K
影响因子：
3.5
作者：
Chamberlain, Christopher M.;Ranum, Laura P. W.
通讯作者：
Ranum, Laura P. W.
DOI：
10.1073/pnas.1605731113
发表时间：
2016-09-27
影响因子：
11.1
作者：
Hammond, Suzan M.;Hazell, Gareth;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
4.3
作者：
Arandel L;Polay Espinoza M;Matloka M;Bazinet A;De Dea Diniz D;Naouar N;Rau F;Jollet A;Edom-Vovard F;Mamchaoui K;Tarnopolsky M;Puymirat J;Battail C;Boland A;Deleuze JF;Mouly V;Klein AF;Furling D
通讯作者：
Furling D
影响因子：
16.6
作者：
Cerro-Herreros E;Sabater-Arcis M;Fernandez-Costa JM;Moreno N;Perez-Alonso M;Llamusi B;Artero R
通讯作者：
Artero R