Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in Duchenne muscular dystrophy.
Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in Duchenne muscular dystrophy.
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野生型小鼠模型筛选反义寡核苷酸在杜氏肌营养不良症中的外显子跳跃功效
DOI：
10.1371/journal.pone.0111079
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Cao L;Han G;Gu B;Yin H
一个容易获得的动物模型对于快速确定杜氏肌营养不良症（DMD）的有效治疗是必不可少的，杜氏肌营养不良症是一种由缺乏肌营养不良蛋白引起的破坏性神经肌肉疾病，其由DMD基因中的框架破坏突变引起。目前，mdx小鼠是反义寡核苷酸（AO）介导的外显子跳读临床前研究中最常用的模型，具有轻度表型。然而，mdx小鼠群体的可及性，特别是在发展中国家，可能会限制研究。因此，在这项研究中，我们探索了使用野生型小鼠作为模型来建立各种DMD AO化学物质及其缀合物的外显子跳跃效率的可行性。肌内研究了四种不同品系的野生型小鼠和六种不同的AO化学，结果表明，所有测试的AO都实现了与mdx小鼠相同的外显子跳跃效率。值得注意的是，在C57 BL 6和C3 H和mdx小鼠中获得的外显子跳跃水平最接近匹配，其次是ICR和BALB/C小鼠。系统验证显示，野生型小鼠对AO介导的外显子跳跃的反应性低于mdx小鼠。我们的研究首次提供了野生型小鼠可以作为评估DMD AO外显子跳跃效率的合适模型的证据，其敏感性与mdx小鼠相似，这一发现可以进一步加速有效DMD AO的开发。
A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD), a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO)-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs.
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影响因子：
12.4
作者：
Heemskerk, Hans;de Winter, Christa;van Kuik, Petra;Heuvelmans, Niki;Sabatelli, Patrizia;Rimessi, Paola;Braghetta, Paola;van Ommen, Gert-Jan B.;de Kimpe, Sjef;Ferlini, Alessandra;Aartsma-Rus, Annemieke;van Deutekom, Judith C. T.
通讯作者：
van Deutekom, Judith C. T.
影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
影响因子：
3.5
作者：
Heemskerk, Hans A.;de Winter, Christa L.;Aartsma-Rus, Annemieke
通讯作者：
Aartsma-Rus, Annemieke
影响因子：
168.9
作者：
Cirak, Sebahattin;Arechavala-Gomeza, Virginia;Guglieri, Michela;Feng, Lucy;Torelli, Silvia;Anthony, Karen;Abbs, Stephen;Garralda, Maria Elena;Bourke, John;Wells, Dominic J.;Dickson, George;Wood, Matthew J. A.;Wilton, Steve D.;Straub, Volker;Kole, Ryszard;Shrewsbury, Stephen B.;Sewry, Caroline;Morgan, Jennifer E.;Bushby, Kate;Muntoni, Francesco
通讯作者：
Muntoni, Francesco
影响因子：
82.9
作者：
Alter, J;Lou, F;Lu, QL
通讯作者：
Lu, QL