Warren Travis K, Whitehouse Chris A, Wells Jay, Welch Lisa, Heald Alison E, Charleston Jay S, Sazani Pete, Reid St Patrick, Iversen Patrick L, Bavari Sina
Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
mBio. 2015 Feb 10;6(1):e02344-14. doi: 10.1128/mBio.02344-14.
Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures.
Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval.
埃博拉病毒（EBOV）可导致人类和非人类灵长类动物患上严重疾病，死亡率很高，并且不断在新的地理位置出现，包括西非的几个国家，目前那里正在发生大规模疫情。磷酰二胺吗啉代寡聚物（PMO）是一种合成反义分子，能够以序列特异性方式靶向mRNA，并通过空间位阻抑制翻译。我们之前表明，使用靶向VP35和VP24组合的PMO可保护恒河猴免受致命的EBOV感染。令人惊讶的是，本研究发现，单独靶向VP24的PMOplus化合物足以提供针对致命EBOV感染的保护，但单独靶向VP35的PMOplus则没有保护作用。这项研究进一步证实了最近的数据，表明VP24可能是EBOV编码的关键毒力因子，并表明VP24是开发有效抗EBOV对策的一个有前景的靶点。
目前，几个西非国家正遭受埃博拉病毒（EBOV）疫情的蹂躏，这场疫情已成为一场重大流行病，不仅影响这些非洲国家，还波及欧洲和美国。由于目前尚无针对埃博拉病毒病的许可治疗方法或疫苗，更好地了解EBOV的毒力机制对于开发有效治疗方法很重要。这项针对两种不同EBOV蛋白的mRNA单独及联合使用磷酰二胺吗啉代寡聚物（PMO）的研究表明，在EBOV致死性灵长类动物模型中，靶向单一蛋白可有效带来显著的生存益处。如果只需要一种PMO而不是联合使用，那么未来开发针对EBOV有效的PMO将会更简单，特别是在监管审批方面。
