Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers.
The filoviruses Marburg virus and Ebola virus (EBOV) quickly outpace host immune responses and cause hemorrhagic fever, resulting in case fatality rates as high as 90% in humans and nearly 100% in nonhuman primates. The development of an effective therapeutic for EBOV is a daunting public health challenge and is hampered by a paucity of knowledge regarding filovirus pathogenesis. This report describes a successful strategy for interfering with EBOV infection using antisense phosphorodiamidate morpholino oligomers (PMOs). A combination of EBOV-specific PMOs targeting sequences of viral mRNAs for the viral proteins (VPs) VP24, VP35, and RNA polymerase L protected rodents in both pre- and post-exposure therapeutic regimens. In a prophylactic proof-of-principal trial, the PMOs also protected 75% of rhesus macaques from lethal EBOV infection. The work described here may contribute to development of designer, "druggable" countermeasures for filoviruses and other microbial pathogens.
Warfield
Kelly L
KL
US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
Swenson
Dana L
DL
Olinger
Gene G
GG
Nichols
Donald K
DK
Pratt
William D
WD
Blouch
Robert
R
Stein
David A
DA
Aman
M Javad
MJ
Iversen
Patrick L
PL
Bavari
Sina
S
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology*; D029043:Ebolavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D060172:Morpholinos; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication / Q000187:drug effects
D016375:Antisense Elements (Genetics); D009025:Morpholines; D060172:Morpholinos; D012367:RNA, Viral; C446938:VP24 protein, Ebola virus; C080980:VP35 protein, filovirus; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins