Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference

Thomas Geisbert, Lisa E. Hensley, Elliott Kagan, Erik Zhaoying Yu, Joan B. Geisbert, Kathleen Daddario-DiCaprio, Elizabeth A. Fritz, Peter B. Jahrling, Kevin McClintock, Janet R. Phelps, Amy C H Lee, Adam Judge, Lloyd B. Jeffs, Ian MacLachlan

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

Background. Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Methods. Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Results. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Conclusions. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

Original languageEnglish (US)
Pages (from-to)1650-1657
Number of pages8
JournalJournal of Infectious Diseases
Volume193
Issue number12
DOIs
StatePublished - Jun 15 2006
Externally publishedYes

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Ebolavirus
RNA Interference
Small Interfering RNA
Democratic Republic of the Congo
Ebola Hemorrhagic Fever
Guinea Pigs
Polyethyleneimine
Viremia
Nucleic Acids
Lipids
Gene Pool
DNA-Directed RNA Polymerases
Antiviral Agents
Fever
Technology
Gene Expression
Therapeutics
Genes

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Geisbert, T., Hensley, L. E., Kagan, E., Yu, E. Z., Geisbert, J. B., Daddario-DiCaprio, K., ... MacLachlan, I. (2006). Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference. Journal of Infectious Diseases, 193(12), 1650-1657. https://doi.org/10.1086/504267

Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference. / Geisbert, Thomas; Hensley, Lisa E.; Kagan, Elliott; Yu, Erik Zhaoying; Geisbert, Joan B.; Daddario-DiCaprio, Kathleen; Fritz, Elizabeth A.; Jahrling, Peter B.; McClintock, Kevin; Phelps, Janet R.; Lee, Amy C H; Judge, Adam; Jeffs, Lloyd B.; MacLachlan, Ian.

In: Journal of Infectious Diseases, Vol. 193, No. 12, 15.06.2006, p. 1650-1657.

Research output: Contribution to journalArticle

Geisbert, T, Hensley, LE, Kagan, E, Yu, EZ, Geisbert, JB, Daddario-DiCaprio, K, Fritz, EA, Jahrling, PB, McClintock, K, Phelps, JR, Lee, ACH, Judge, A, Jeffs, LB & MacLachlan, I 2006, 'Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference', Journal of Infectious Diseases, vol. 193, no. 12, pp. 1650-1657. https://doi.org/10.1086/504267
Geisbert, Thomas ; Hensley, Lisa E. ; Kagan, Elliott ; Yu, Erik Zhaoying ; Geisbert, Joan B. ; Daddario-DiCaprio, Kathleen ; Fritz, Elizabeth A. ; Jahrling, Peter B. ; McClintock, Kevin ; Phelps, Janet R. ; Lee, Amy C H ; Judge, Adam ; Jeffs, Lloyd B. ; MacLachlan, Ian. / Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference. In: Journal of Infectious Diseases. 2006 ; Vol. 193, No. 12. pp. 1650-1657.
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N2 - Background. Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Methods. Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Results. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Conclusions. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

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