...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nucleic Acid Therapeutics >Lowering Mutant Huntingtin Using Tricyclo-DNA Antisense Oligonucleotides As a Therapeutic Approach for Huntington's Disease
【24h】

Lowering Mutant Huntingtin Using Tricyclo-DNA Antisense Oligonucleotides As a Therapeutic Approach for Huntington's Disease

机译：使用三环 - DNA反义寡核苷酸降低突变亨廷汀作为亨廷顿疾病的治疗方法

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of huntingtin gene (HTT) encoding for a toxic polyglutamine protein. This disease is characterized by motor, psychiatric, and cognitive impairments. Currently, there is no disease modifying treatment. However, reducing the expression of the huntingtin protein (HTT) using antisense oligonucleotides (ASOs) has been shown as a promising therapeutic strategy. In this study, we explore the therapeutic potential of ASO made of tricyclo-DNA (tcDNA), a conformationally constrained DNA analog, to silence HTT. We used a gapmer ASO, containing central DNA nucleotides flanked by tcDNA modifications on 5 ' and 3 ' ends, allowing the recruitment of RNAse H and subsequent degradation of the messenger RNA. After transfection of tcDNA-ASO in patient-derived fibroblast cell lines, we show a strong decrease of HTT mRNA and protein levels. As a control, 2 ' O-methyl-RNA targeting the same region of HTT was also tested and did not induce a significant effect. tcDNA-ASO were also evaluated in vivo in the YAC128 mice, containing the full-length human HTT gene with 128 CAG repeat expansion. Single intracerebroventricular (ICV) injections of tcDNA induce a significant decrease of HTT messenger and protein levels in the cortex, hippocampus, striatum, and cerebellum of treated mice. tcDNA-ASO were found well distributed in the central nervous system (CNS) and show long lasting effect with protein levels still low, 12 weeks after a single ICV injection. This proof of concept study suggests the therapeutic potential of gapmer tcDNA ASO to downregulate huntingtin in vitro and in vivo.
机译：亨廷顿的疾病是一种神经变性障碍，由亨廷顿基因（HTT）的第一个术语中的CAG重复膨胀引起的，所述亨廷顿基因（HTT）编码毒性多谷氨酰胺蛋白。这种疾病的特征在于电动机，精神病和认知障碍。目前，没有疾病修饰治疗。然而，已经显示了使用反义寡核苷酸（ASOS）的亨廷顿蛋白（HTT）的表达作为有前途的治疗策略。在这项研究中，我们探讨了由三环 - DNA（TCDNA）制成的ASO的治疗潜力，沉默HTT。我们使用了Gapmer ASO，含有在5'和3'末端的TCDNA修饰中侧翼的中央DNA核苷酸，允许募集RNase H并随后的信使RNA降解。在患者衍生的成纤维细胞系中转染TCDNA-aso后，我们显示出HTT mRNA和蛋白质水平的强烈降低。作为一种对照，还测试了靶向相同区域的2'O-甲基-RNA，并没有诱导显着效果。还在Yac128小鼠中体内评估TCDNA-ASO，含有128个CAG重复膨胀的全长人HTT基因。单胞内脑室（ICV）的TCDNA注射诱导皮质，海马，纹状体和治疗小鼠的小脑中HTT信使和蛋白质水平的显着降低。在中枢神经系统（CNS）中发现TCDNA-ASO良好分布，并显示蛋白质水平仍然存在较长的效果，在单一ICV注射后12周。这种概念研究证明表明Gapmer TCDNA Aso的治疗潜力在体外和体内下调亨廷汀。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号