siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

Emily P. Thi, Chad Mire, Amy C.H. Lee, Joan B. Geisbert, Raul Ursic-Bedoya, Krystle N. Agans, Marjorie Robbins, Daniel J. Deer, Robert Cross, Andrew S. Kondratowicz, Karla A. Fenton, Ian MacLachlan, Thomas Geisbert

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5 Scopus citations

Abstract

Ebolaviruses and marburgviruses belong to the family Filoviridae and cause high lethality in infected patients. There are currently no licensed filovirus vaccines or antiviral therapies. The development of broad-spectrum therapies against members of the Marburgvirus genus, including Marburg virus (MARV) and Ravn virus (RAVV), is difficult because of substantial sequence variability. RNAi therapeutics offer a potential solution, as identification of conserved target nucleotide sequences may confer activity across marburgvirus variants. Here, we assessed the therapeutic efficacy of lipid nanoparticle (LNP) delivery of a single nucleoprotein–targeting (NP-targeting) siRNA in nonhuman primates at advanced stages of MARV or RAVV disease to mimic cases in which patients begin treatment for fulminant disease. Sixteen rhesus monkeys were lethally infected with MARV or RAVV and treated with NP siRNA-LNP, with MARV-infected animals beginning treatment four or five days after infection and RAVV-infected animals starting treatment three or six days after infection. While all untreated animals succumbed to disease, NP siRNA-LNP treatment conferred 100% survival of RAVV-infected macaques, even when treatment began just 1 day prior to the death of the control animals. In MARV-infected animals, day-4 treatment initiation resulted in 100% survival, and day-5 treatment resulted in 50% survival. These results identify a single siRNA therapeutic that provides broad-spectrum protection against both MARV and RAVV.

Original languageEnglish (US)
Pages (from-to)4437-4448
Number of pages12
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thi, E. P., Mire, C., Lee, A. C. H., Geisbert, J. B., Ursic-Bedoya, R., Agans, K. N., Robbins, M., Deer, D. J., Cross, R., Kondratowicz, A. S., Fenton, K. A., MacLachlan, I., & Geisbert, T. (2017). siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease. Journal of Clinical Investigation, 127(12), 4437-4448. https://doi.org/10.1172/JCI96185