Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice.
Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice.
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DOI：
10.1002/ana.25264
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发表时间：
2018-07
影响因子：
11.2
通讯作者：
Paulson HL
中科院分区：
文献类型：
--
作者：
McLoughlin HS;Moore LR;Chopra R;Komlo R;McKenzie M;Blumenstein KG;Zhao H;Kordasiewicz HB;Shakkottai VG;Paulson HL
脊髓小脑性共济失调3型（SCA3），也称为Machado-Joseph病，是最常见的显性遗传性共济失调。尽管对这种CAG重复/聚谷氨酰胺扩增疾病的了解有所进展，但仍然没有治疗方法可以改变其进行性致命过程。在此，我们研究了一种靶向SCA3疾病基因ATXN3的反义寡核苷酸（ASO）是否可以预防SCA3小鼠模型的分子、神经病理、电生理和行为特征。从体内筛选到的靶向顶部atxn3的ASO被注射到早期症状的转基因SCA3小鼠脑室内，这些小鼠表达了完整的人类疾病基因并概括了关键的疾病特征。在8周龄单次ASO治疗后，对小鼠进行了ATXN3抑制和疾病相关病理改变的纵向评估。小鼠在21周时接受额外的重复注射，纵向评估到29周的运动表现。靶向ATXN3的ASO在治疗后8周内实现了聚谷氨酰胺扩增ATXN3的持续减少，并在治疗后至少14周内阻止了ATXN3的寡聚物和核积累。纵向ASO治疗挽救了SCA3小鼠的运动损伤，这种挽救与浦肯野神经元放电频率和后超极化缺陷的恢复有关。这项临床前研究确定了atxn3靶向ASOs作为SCA3疾病改善治疗策略的有效性。这些结果支持进一步开发ASOs用于这种多聚谷氨酰胺疾病以及其他由毒性功能获得引起的主要遗传性疾病的人体临床试验。
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate whether an antisense oligonucleotide (ASO) targeting the SCA3 disease gene, ATXN3, can prevent molecular, neuropathological, electrophysiological and behavioral features of the disease in a mouse model of SCA3. The top ATXN3-targeting ASO from an in vivo screen was injected intracerebroventricularly into early symptomatic transgenic SCA3 mice that express the full human disease gene and recapitulate key disease features. Following a single ASO treatment at 8 weeks of age, mice were evaluated longitudinally for ATXN3 suppression and rescue of disease-associated pathological changes. Mice receiving an additional repeat injection at 21 weeks were evaluated longitudinally up to 29 weeks for motor performance. The ATXN3-targeting ASO achieved sustained reduction of polyglutamine-expanded ATXN3 up to 8 weeks after treatment and prevented oligomeric and nuclear accumulation of ATXN3 up to at least 14 weeks after treatment. Longitudinal ASO therapy rescued motor impairment in SCA3 mice, and this rescue was associated with a recovery of defects in Purkinje neuron firing frequency and afterhyperpolarization. This preclinical study established efficacy of ATXN3-targeted ASOs as a disease-modifying therapeutic strategy for SCA3. These results support further efforts to develop ASOs for human clinical trials in this polyglutamine disease as well as in other dominantly inherited disorders caused by toxic gain of function.
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DOI：
10.1038/nrn.2017.92
发表时间：
2017-10
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Paulson HL;Shakkottai VG;Clark HB;Orr HT
通讯作者：
Orr HT
影响因子：
16.2
作者：
Kordasiewicz HB;Stanek LM;Wancewicz EV;Mazur C;McAlonis MM;Pytel KA;Artates JW;Weiss A;Cheng SH;Shihabuddin LS;Hung G;Bennett CF;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
5.3
作者：
Hourez, Raphael;Servais, Laurent;Schiffmann, Serge N.
通讯作者：
Schiffmann, Serge N.
影响因子：
5.3
作者：
Bichelmeier, Ulrike;Schmidt, Thorsten;Riess, Olaf
通讯作者：
Riess, Olaf
影响因子：
6.7
作者：
Jimenez-Sanchez, Maria;Thomson, Frances;Zavodszky, Eszter;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.