Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study.
Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study.
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DOI：
10.1016/s0140-6736(10)60357-1
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发表时间：
2010-05-29
期刊：
影响因子：
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通讯作者：
Maclachlan I
中科院分区：
文献类型：
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作者：
Geisbert TW;Lee AC;Robbins M;Geisbert JB;Honko AN;Sood V;Johnson JC;de Jong S;Tavakoli I;Judge A;Hensley LE;Maclachlan I
我们以前表明，小干扰RNA（siRNA）靶向扎伊尔埃博拉病毒（ZEBOV）RNA聚合酶L蛋白配制在稳定的核酸-脂质颗粒（SNALP）完全保护豚鼠时，致命ZEBOV挑战后不久给药。尽管ZEBOV感染的啮齿动物模型可用于筛选前瞻性对策，但它们通常不可用于预测更严格的非人灵长类动物模型中的功效。因此，我们评估了修饰的非免疫刺激性siRNA在ZEBOV出血热的一致致死非人灵长类动物模型中的功效。在SNALP中配制靶向ZEBOV L聚合酶（EK-1 mod）、病毒蛋白（VP）24（VP 24 -1160 mod）和VP 35（VP 35 -855 mod）的修饰的siRNA的组合。在用ZEBOV攻击后30分钟后和第1、3和5天，向一组猕猴（n=3）给予这些合并的抗ZEBOV siRNA（每剂量2 mg/kg，推注静脉内输注）。第二组猕猴（n=4）在用ZEBOV攻击后30分钟后和第1、2、3、4、5和6天给予合并的抗ZEBOV siRNA。给予合并的抗ZEBOV siRNA的四次暴露后处理的三只恒河猴中的两只（66%）被保护免于致死性ZEBOV感染，而给予七次暴露后处理的所有猕猴都被保护。第二项研究中的治疗方案耐受性良好，肝酶发生轻微变化，可能与病毒感染有关。在非人灵长类动物中针对ZEBOV的这种完全的暴露后保护提供了用于治疗ZEBOV诱导的出血热的模型。这些数据显示了RNA干扰作为埃博拉病毒感染者的有效治疗策略的潜力，并表明这种策略也可能用于治疗其他新出现的病毒感染。国防威胁降低局。
We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. Defense Threat Reduction Agency.