title: Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference.
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.
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011, USA. tom.geisbert@amedd.army.mil
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.forename: Elliott
authors.initials: E
authors.lastname: Kagan
authors.forename: Erik Zhaoying
authors.initials: EZ
authors.lastname: Yu
authors.forename: Joan B
authors.initials: JB
authors.lastname: Geisbert
authors.forename: Kathleen
authors.initials: K
authors.lastname: Daddario-DiCaprio
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fritz
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jahrling
authors.forename: Kevin
authors.initials: K
authors.lastname: McClintock
authors.forename: Janet R
authors.initials: JR
authors.lastname: Phelps
authors.forename: Amy C H
authors.initials: AC
authors.lastname: Lee
authors.forename: Adam
authors.initials: A
authors.lastname: Judge
authors.forename: Lloyd B
authors.initials: LB
authors.lastname: Jeffs
authors.forename: Ian
authors.initials: I
authors.lastname: MacLachlan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics*; D006168:Guinea Pigs; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D016898:Interferon-alpha / Q000097:blood; D016899:Interferon-beta / Q000097:blood; D008081:Liposomes; D011094:Polyethyleneimine; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics; D016019:Survival Analysis; D010948:Viral Plaque Assay; D014766:Viremia
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D008081:Liposomes; D034741:RNA, Small Interfering; D016899:Interferon-beta; D011094:Polyethyleneimine; D012324:RNA-Dependent RNA Polymerase