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 2

NP-718m–LNP treatment effectively controls MARV or RAVV viral replication in blood and tissues.

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NP-718m–LNP treatment effectively controls MARV or RAVV viral replicatio...
(A) NP-718m–LNP treatment mediates up to 4 log reductions in viremia in MARV-infected NHPs when compared with untreated controls. Protection was greatest when treatment was initiated at earlier p.i. time points. n = 4 treated animals and n = 1 untreated control each for 1 study 4 days p.i. and 1 study 5 days p.i. *P = 0.0159, by 1-tailed, unpaired t test (day 8). (B) Similar reductions in viremia were also observed in RAVV-infected animals treated with NP-718m alone or in a cocktail with NP-143m. n = 2 for NP-718m–LNP and NP-718m plus NP-143m–LNP treatment groups 3 days p.i.. n = 4 treated animals for the day-6 p.i. study. n = 1 untreated control for each study. NP-718m treatment resulted in reductions in viral RNA present in the blood for (C) MARV (*P = 0.0033, by 1-tailed, unpaired t test; day 8) and (D) RAVV, as assessed by viral RNA qRT-PCR. 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. 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. Treatment was also able to control RAVV (E) and MARV (F) viral replication in tissues, including those in immune-privileged sites such as the reproductive organs, brain, and eye. The lower limit of quantification (LLOQ) for viral RNA qRT-PCR was 1 × 105 GEq/ml or GEq/g. LN, lymph node.