RNAi-mediated gene silencing in non-human primates
RNAi-mediated gene silencing in non-human primates
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DOI：
10.1038/nature04688
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发表时间：
2006-05-04
期刊：
影响因子：
64.8
通讯作者：
MacLachlan, I
中科院分区：
文献类型：
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作者：
Zimmermann, TS;Lee, ACH;MacLachlan, I
利用RNA干扰(RNAi)途径沉默致病基因的机会为开发针对现有药物无法解决的靶点的疗法带来了巨大的希望(1，2)。虽然在局部传递小干扰RNA(SiRNAs)(3-5)后靶基因的体内沉默的例子很多，但仍然只有少数报道RNAi介导的沉默响应于系统的siRNA传递(6-8)，并且没有关于非啮齿动物物种的全身疗效的报道。在这里，我们展示了当siRNAs以脂质体形式系统地传递时，可以在非人类灵长类动物中沉默疾病靶标载脂蛋白B(ApoB)。将载脂蛋白B特异的siRNAs包裹在稳定的核酸脂质颗粒(SNALP)中，静脉注射给食蟹猴，剂量为1或2.5 mg kg(-1)。单次注射siRNA后48h，肝脏APOB信使RNA表达呈剂量依赖性沉默，最大沉默达90%。这种沉默效应是由于APOB mRNA在RNAi机制预测的位置发生切割的结果。ApoB蛋白、血清胆固醇和低密度脂蛋白水平在治疗后24 h即可显著降低，最高剂量的siRNA可持续11天，显示出即时、有效和持久的生物学效应。我们的发现表明，在非人类灵长类动物中，RNAi介导的基因沉默在临床上是相关的，支持RNAi疗法作为一种潜在的新的药物类别。
The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines(1,2). Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs)(3-5), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA(6-8), and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.