I admit to some trepidation about the diseases that may be harbored in my backyard. For example, do the mice in my yard and, despite my and my cats’ efforts, in my house carry deer ticks that harbor the bacterium Borrelia burgdorferi, which causes Lyme disease? Should I be keeping an eye on the vitality of the birds around my property and density of my local mosquito population for potential risk of West Nile Virus transmission? As troublesome as these infections can be, mortality is low for infected humans. Contrast that with the mortality rate of up to 90% for the filoviruses Ebola and Marburg. I find it easy to dismiss these viruses because the reservoir (asymptomatic host) is not in the Upper Midwest but rather Africa, but the tragedy of the Ebola outbreak in the West African countries of Liberia, Sierra Leone and Guinea demonstrates the number of lives lost in an epidemic. Currently, there is no therapy or vaccine to treat these deadly viruses other than transferring antibodies from survivors to those infected. Therefore, the article in Science Translational Medicine about an antiviral treatment that protected macaques injected with a lethal dose of Marburg virus was welcome news.
Previously, this research group had evidence that a Marburg virus (MARV) siRNA NP-718m encapsulated in lipid nanoparticles (LNPs) inhibited viral replication in vitro and in infected guinea pigs. To further explore how effective this treatment might be, 21 rhesus macaques were inoculated with a lethal dose of MARV strain Angola, one of the deadliest strains, and partitioned into four treatment groups. At 30–45 minutes or 24, 48 or 72 hours, NP-718m treatment, sham treatment (siRNA targeting firefly luciferase) or no treatment began, repeated once a day for the next six days. Each treatment group of four macaques had at least one control animal (either no treatment or sham treatment). The researchers monitored infected animal survival and discovered that all treated animals survived regardless of the timing of the NP-718m treatment; all control animals succumbed to infection after 8–9 days. In addition, the clinical measures of disease did not change for NP-718m-treated animals, staying at baseline during the course of the 28-day experiment. The control macaques showed signs of advanced disease by days 7–9.
Serum samples were taken from control and treated macaques, and the number of viral particles present was assessed using a plaque assay. The macaques treated with NP-718m had 5–7 orders of magnitude less virus in their serum compared with control animals, indicating the treatment significantly reduced viral load. Viral RNA isolated from serum taken at various times during infection or from tissue (e.g., liver and spleen) and amplified using RT-qPCR showed similar results: All macaques treated with NP-718m in LPNs had lower peak viral RNA levels compared to control animals.
One indicator of MARV infection is a rise in liver damage markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Testing macaque serum for these markers indicated that NP-718m-treated animals either had little damage or transient damage with less severity compared to control animals. One of the hallmarks of Marburg virus infection is hemorrhaging due to inhibition of blood coagulation. By assessing coagulation parameters, the scientists learned that NP-718m treatment minimized any increase in coagulation time in treated versus untreated animals. Furthermore, tissue examined for MARV-induced lesions and viral protein immunostaining showed no lesions and did not react with anti-MARV VP40 protein in NP-718m-treated macaques, but lesions and positive staining occurred in tissues from control animals.
The preliminary work from Thi et al. demonstrates the effectiveness of NP-718m, an siRNA, encapsulated in LNPs as a treatment for Marburg virus infection. Interestingly, this treatment was effective even three days after infection when clinical symptoms begin to manifest. Although these experiments were not blinded and the population tested was small, the fact that all 16 treated macaques survived challenged from MARV-Angola while all five control animals did not is promising. As frightening as viruses like Marburg and Ebola can be, this experiment shows we are one step closer to minimizing suffering from these devastating viral hemorrhagic fevers.
Thi, E.P., Ursic-Bedoya, R., Geisbert, J.B., Lee, A.C.H., Agans, K.N., Robbins, M., Deer, D.J., Fenton, K.A., MacLachlan, I. and Geisbert, T.W. (2014) Marburg virus infection in nonhuman primates: Therapeutic treatment by lipid-encapsulated siRNA, Science Translational Medicine, 6 (250) 250ra116-250ra116. DOI: http://dx.doi.org/10.1126/scitranslmed.3009706
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