Running interference on hemorrhagic fever

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaar4433
DOI: 10.1126/scitranslmed.aar4433


A siRNA-based therapy for Marburg viruses shows promise.

Filoviruses, such as Ebola and Marburg virus, are emerging infections that cause hemorrhagic fever, which is lethal in 30 to 90% of cases. At present, incidence is largely confined to Africa, but sporadic cases in North America and Europe due to international air travel have laid bare the potential reach of these infections. Ebola virus has captured the most public attention given the outbreak that claimed over 10,000 lives between 2013 and 2016. However, Marburg viruses are equally deadly, as evidenced by the small outbreak in eastern Uganda under way right now. Therapies for infected individuals, particularly for patients with Marburg viruses, remain largely supportive. In a recent paper, Thi et al. report progress on a small interfering RNA (siRNA)–based therapy for two members of the marburgvirus genus: the synonymous Marburg virus and Ravn virus. The idea of siRNA therapy is to slow the production of viral proteins within infected cells, thereby interfering with the virus life cycle and giving the patient’s immune system a chance to catch up. NP-718m-LNP is a lipid-encapsulated siRNA that targets the viral nucleoprotein (NP) of both Marburg and Ravn viruses that had already shown efficacy in rodents and primates when administered before onset of clinical symptoms. The new study, conducted in lethally infected rhesus macaques, tested NP-718m-LNP that was administered after the animals were symptomatic and viremic. In this setting, NP-718m-LNP conferred 50 to 100% survival with efficacy attenuating as time and organ failure progressed. The results suggest that there is a clinical window in symptomatic patients where siRNA-based therapy for Marburg hemorrhagic fever could work. How large that window is remains unclear: A small phase-II trial testing siRNA therapy against Ebola virus in patients with advanced disease recently showed safety but not clear efficacy. Moreover, deploying an IV-based siRNA therapeutic for mass treatment of hemorrhagic fever in resource-limited areas would be challenging. Nevertheless, the results of Thi et al. are an important advance for making siRNA a viable salvage therapy for hemorrhagic fever.

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