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 3

NP-718m–LNP treatment ameliorates disease symptoms in MARV or RAVV HF.

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NP-718m–LNP treatment ameliorates disease symptoms in MARV or RAVV HF. (...
(A) Clinical scores of untreated or NP-718m–LNP–treated MARV-infected animals. n = 4 treated animals and n = 1 untreated control each for the MARV day-4 p.i. study and the MARV day-5 p.i. study. (B) Clinical scores of untreated or NP-718m–LNP–treated animals lethally infected with RAVV. n = 2 for NP-718m–LNP and NP-718m plus NP-143m–LNP treatment groups for the RAVV day-3 p.i. study and n = 4 treated animals for the RAVV day-6 p.i. study. n = 1 untreated control for each study. Scoring changes measured from baseline included posture and activity level, attitude and behavior, food and water intake, weight, respiration, and disease manifestations such as visible rash, hemorrhage, ecchymosis, or flushed skin. A score of ≥ 9 indicated that an animal met the criteria for euthanasia. (C) Animals treated with NP-718m showed amelioration of liver dysfunction typical of MARV infection. (D) NP-718m–LNP treatment protected against liver dysfunction in macaques lethally infected with RAVV. (E) NP-718m–LNP treatment ameliorated kidney dysfunction resulting from MARV disease. (F) Both NP-718m alone or in a siRNA cocktail with NP-143m conferred similar protection against kidney dysfunction in RAVV-infected NHPs.