siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease
Emily P. Thi, … , Ian MacLachlan, Thomas W. Geisbert
Emily P. Thi, … , Ian MacLachlan, Thomas W. Geisbert
Published December 1, 2017; First published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4437-4448. https://doi.org/10.1172/JCI96185.
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Categories: Research Article Infectious disease Virology

siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

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.

Authors

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

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Figure 6

Comparison of MARV pathology and antigen in representative tissues of rhesus monkeys either treated or not with NP-718m–LNP.

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Comparison of MARV pathology and antigen in representative tissues of rh...
(A and I) Spleen: diffuse lymphoid depletion of the white pulp and fibrin deposition in the red pulp in a MARV-infected control animal and a nonsurviving NP-718m–LNP–treated animal. (C and K) Spleen: diffuse cytoplasmic immunolabeling of dendriform mononuclear cells in the red and white pulp of a MARV-infected control animal and a nonsurviving NP-718m–LNP–treated animal. No overt lesion (E) or immunolabeling (G) was observed in the spleen of a surviving NP-718m–LNP–treated animal. (B and J) Liver: multifocal necrotizing hepatitis, sinusoidal leukocytosis, and eosinophilic cytoplasmic inclusion bodies in a MARV-infected control animal and a nonsurviving NP-718m–LNP–treated animal. (D and L) Liver: diffuse cytoplasmic immunolabeling (brown color) of sinusoidal lining cells, Kupffer cells, and hepatocytes in a nonsurviving NP-718m–LNP–treated animal. No overt lesion (F) or immunolabeling (H) was observed in liver from a surviving NP-718m–LNP–treated animal. All representative images (original magnification, ×20) are from surviving NP-718m-7–treated animal, nonsurviving NP-718m-8–treated animal, and an untreated control animal 5 days p.i. Ag, antigen.