Evaluation of a PPMO Inhibitor of Lassa Virus Infection and Disease in a Guinea Pig Model

PPMO对豚鼠拉萨病毒感染和疾病抑制作用的评价 摘要： 拉沙热(LF)是由感染拉萨病毒(LASV)引起的，目前是人类的主要疾病问题 在西非大部分地区，每年造成数千人死亡。最近爆发的低频肺炎的特征是 与以前的疫情相比，病例数量增加，地理足迹更大，并构成 日益严重的公共卫生危机。此外，输入到非流行国家的LF病例数量为 LASV正在增长，也有人担心LASV可能被用作生物战的毒剂。到目前为止还没有 没有获得许可的疫苗或特定的抗病毒疗法来干预LASV感染和治疗患者 而目前的治疗方案疗效较差。因此，有一种迫在眉睫的紧急医疗需求 寻找新的抗病毒化合物来解决LASV。多肽偶联的磷二酸吗啉低聚物 PPMO是一类单链核酸类似物，可以很容易地进入细胞并干扰 通过立体阻断互补RNA来产生病毒蛋白。PPMO已经表现出相当大的 在体外和体内对一些RNA病毒的抗病毒效果，包括几种阿拉伯病毒。我们 建议合成两个针对LASV基因组末端高度保守的RNA序列的PPMO 基因组。每个PPMO将在非细胞毒性剂量范围内接受测试，以对抗几种基因上的- 不同的LASV毒株。在体外表现出最高抗病毒效果的PPMO将被推进到 在LASV病的豚鼠模型上进行测试。动物体重、温度、外观和行为，以及 将监测几个组织中的死亡率和病毒滴度。这项研究的目的是评估 PPMO在严重LASV疾病的小动物模型中降低发病率和死亡率。如果成功，则 该项目将生产一种抑制剂，这种抑制剂将立即用作对抗任何菌株的研究试剂 作为LASV的候选药物，可进一步发展成为治疗人类LASV感染的药物。

Evaluation of a PPMO Inhibitor of Lassa Virus Infection and Disease in a Guinea Pig Model ABSTRACT: Lassa fever (LF) is caused by infection with Lassa virus (LASV), and is currently a major human disease problem in much of West Africa, causing thousands of deaths annually. Recent outbreaks of LF have been characterized by an increased number of cases and larger geographic footprint compared to previous outbreaks, and constitute a burgeoning public health crisis. In addition, the number of LF cases imported into non-endemic countries is growing, and there is also concern that LASV could be used as an agent of biological warfare. There is as yet no licensed vaccine or specific antiviral therapeutic to intervene against LASV-infections and treat patients with LF, and current treatment options have poor efficacy. There is therefore an immediate and critical medical need for new antiviral compounds to address LASV. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are a class of single-stranded-nucleic acid analogs that can enter cells readily and interfere with the production of viral proteins through steric blocking of complementary RNA. PPMO have shown considerable antiviral efficacy in vitro and in vivo against a number of RNA viruses, including several arenaviruses. We propose to synthesize two PPMO targeting highly conserved RNA sequences in the genomic termini of the LASV genome. Each PPMO will be tested in a non-cytotoxic dose-range for antiviral activity against several genetically- disparate strains of LASV. The PPMO exhibiting the highest antiviral efficacy in vitro will then be advanced to testing in a guinea pig model of LASV disease. Animal weight, temperature, appearance and behavior, along with mortality and viral titer in several tissues will be monitored. This study is designed to evaluate the ability of PPMO to reduce morbidity and mortality in a small-animal model of of severe LASV-disease. If successful, the project will produce an inhibitor that would be immediately useful as a research reagent against any strain of LASV and as a candidate for further development as a therapeutic agent against LASV infections in humans.