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Updated: Jun 14, 2025

MISSION esiRNA for RNAi Screening in Mammalian Cells

MISSION esiRNA for RNAi Screening in Mammalian Cells

Published on: May 12, 2010

选择性和非选择性C9ORF72针对in vivo活性的siRNAs的识别

James W Gilbert¹, Zachary Kennedy¹, Bruno M D C Godinho¹

¹RNA Therapeutic Institute, Worcester, MA 01655, USA.

Molecular therapy. Nucleic acids

|September 5, 2024

概括

与小干扰RNA (siRNA) 的RNA干扰 (RNAi) 有效地降低了C9orf72表达和有毒二蛋白在肌缩侧硬化症 (ALS) 和前性痴呆症 (FTD) 的小鼠模型中. 这种方法对治疗这些神经退行性疾病充满希望.

科学领域:

神经科学是一个神经科学.
遗传学遗传学是一个
在RNA治疗方面,RNA疗法.

背景情况:

在C9ORF72中,六核酸重复扩张 (HRE) 是肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 的主要遗传原因.
拟议的疾病机制包括C9ORF72哈普洛缺陷,RNA焦点的形成和二重复 (DPR) 蛋白质的产生.
目前的治疗策略有限,需要新的方法.

研究的目的:

研究小干扰RNAs (siRNAs) 作为C9ORF72相关ALS和FTD的治疗策略的潜力.
为了识别针对不同C9ORF72转录变异的疾病修饰siRNA.
在相关疾病模型中评估siRNAs在降低C9ORF72表达和下游病理特征方面的有效性.

主要方法:

使用记者分析和来自C9-ALS/FTD小鼠模型的初级皮质神经元对各种C9ORF72转录进行了超过150个化学稳定siRNA的选.
评估报告者测定中的siRNA疗效与本地细胞环境相比,考虑到mRNA可访问性和细胞内定位.
在C9-ALS/FTD小鼠模型中使用双价性siRNAs来测量C9ORF72mRNA和DPR蛋白的减少.

主要成果:

在报告员测定和本地细胞环境中表明siRNA疗效之间缺乏相关性,突显了mRNA可访问性和核定位的重要性.
显示了针对C9ORF72mRNA变异的siRNAs在小鼠模型中显著降低了C9ORF72mRNA表达和DPR蛋白水平.
发现所有C9ORF72转录的siRNA沉默在减少核内mRNA聚合物方面更有效,而不是仅针对含有HRE的转录.

结论:

通过siRNAs进行RNA干扰代表了C9ORF72驱动的ALS和FTD的可行治疗方法.
C9ORF72mRNA的细胞内定位和可访问性显著影响siRNA的疗效.
针对所有C9ORF72转录可能是减少病理聚合物的更有效策略.

关键词:

C9ORF72 肌缩性侧面硬化症,ALS MT:寡核酸:治疗方法和应用.二重复蛋白质的重复蛋白质.前性痴呆症,FTD,前性痴呆症 mRNA局部化的情况.聚核酸的治疗药物.siRNA 是一个RNA.

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