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Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study

BACKGROUND: We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent...

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Autores principales: Geisbert, Thomas W, Lee, Amy CH, Robbins, Marjorie, Geisbert, Joan B, Honko, Anna N, Sood, Vandana, Johnson, Joshua C, de Jong, Susan, Tavakoli, Iran, Judge, Adam, Hensley, Lisa E, MacLachlan, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Ltd. 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138079/
https://www.ncbi.nlm.nih.gov/pubmed/20511019
http://dx.doi.org/10.1016/S0140-6736(10)60357-1
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author Geisbert, Thomas W
Lee, Amy CH
Robbins, Marjorie
Geisbert, Joan B
Honko, Anna N
Sood, Vandana
Johnson, Joshua C
de Jong, Susan
Tavakoli, Iran
Judge, Adam
Hensley, Lisa E
MacLachlan, Ian
author_facet Geisbert, Thomas W
Lee, Amy CH
Robbins, Marjorie
Geisbert, Joan B
Honko, Anna N
Sood, Vandana
Johnson, Joshua C
de Jong, Susan
Tavakoli, Iran
Judge, Adam
Hensley, Lisa E
MacLachlan, Ian
author_sort Geisbert, Thomas W
collection PubMed
description BACKGROUND: We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. METHODS: A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. FINDINGS: Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. INTERPRETATION: This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. FUNDING: Defense Threat Reduction Agency.
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spelling pubmed-71380792020-04-07 Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study Geisbert, Thomas W Lee, Amy CH Robbins, Marjorie Geisbert, Joan B Honko, Anna N Sood, Vandana Johnson, Joshua C de Jong, Susan Tavakoli, Iran Judge, Adam Hensley, Lisa E MacLachlan, Ian Lancet Article BACKGROUND: We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. METHODS: A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. FINDINGS: Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. INTERPRETATION: This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. FUNDING: Defense Threat Reduction Agency. Elsevier Ltd. 2010 2010-05-28 /pmc/articles/PMC7138079/ /pubmed/20511019 http://dx.doi.org/10.1016/S0140-6736(10)60357-1 Text en Copyright © 2010 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Geisbert, Thomas W
Lee, Amy CH
Robbins, Marjorie
Geisbert, Joan B
Honko, Anna N
Sood, Vandana
Johnson, Joshua C
de Jong, Susan
Tavakoli, Iran
Judge, Adam
Hensley, Lisa E
MacLachlan, Ian
Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title_full Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title_fullStr Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title_full_unstemmed Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title_short Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study
title_sort postexposure protection of non-human primates against a lethal ebola virus challenge with rna interference: a proof-of-concept study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138079/
https://www.ncbi.nlm.nih.gov/pubmed/20511019
http://dx.doi.org/10.1016/S0140-6736(10)60357-1
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