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

PPMO 拉沙病毒感染和疾病抑制剂在豚鼠模型中的评价 摘要： 拉沙热（LF）是由拉沙病毒（LASV）感染引起的，是目前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 LF 爆发的特征 与之前的疫情相比，病例数量增加，地理覆盖范围扩大，并构成 一场日益严重的公共卫生危机此外，输入到非流行国家的 LF 病例数为 增长，而且人们还担心 LASV 可能被用作生物战剂。目前为止还有 没有获得许可的疫苗或特定的抗病毒治疗方法来干预 LASV 感染和治疗患有 LASV 感染的患者 LF和目前的治疗方案疗效不佳。因此存在紧急且紧急的医疗需求 寻找新的抗病毒化合物来治疗 LASV。肽缀合二酰胺磷酸吗啉寡聚物 （PPMO）是一类单链核酸类似物，可以很容易地进入细胞并干扰 通过互补 RNA 的空间阻断来生产病毒蛋白。 PPMO 已表现出相当大的 对多种 RNA 病毒（包括几种沙粒病毒）具有体外和体内抗病毒功效。我们 提议合成两个针对 LASV 基因组末端高度保守的 RNA 序列的 PPMO 基因组。每种 PPMO 都将在非细胞毒性剂量范围内进行针对多种基因的抗病毒活性测试。 LASV 的不同毒株。体外表现出最高抗病毒功效的 PPMO 将被进一步推广到 在 LASV 疾病的豚鼠模型中进行测试。动物的体重、温度、外观和行为，以及 将监测多个组织中的死亡率和病毒滴度。本研究旨在评估以下人员的能力： PPMO 可降低严重 LASV 疾病小动物模型的发病率和死亡率。如果成功的话， 该项目将生产一种抑制剂，可立即用作针对任何菌株的研究试剂 LASV 并作为进一步开发作为人类 LASV 感染治疗剂的候选药物。

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.