Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference.
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.
Geisbert
Thomas W
TW
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011, USA. tom.geisbert@amedd.army.mil
Hensley
Lisa E
LE
Kagan
Elliott
E
Yu
Erik Zhaoying
EZ
Geisbert
Joan B
JB
Daddario-DiCaprio
Kathleen
K
Fritz
Elizabeth A
EA
Jahrling
Peter B
PB
McClintock
Kevin
K
Phelps
Janet R
JR
Lee
Amy C H
AC
Judge
Adam
A
Jeffs
Lloyd B
LB
MacLachlan
Ian
I
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
D000998:Antiviral Agents; D016898:Interferon-alpha; D008081:Liposomes; D034741:RNA, Small Interfering; D016899:Interferon-beta; D011094:Polyethyleneimine; D012324:RNA-Dependent RNA Polymerase