title: Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers.
abstract: 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.
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.forename: Dana L
authors.initials: DL
authors.lastname: Swenson
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.forename: Donald K
authors.initials: DK
authors.lastname: Nichols
authors.forename: William D
authors.initials: WD
authors.lastname: Pratt
authors.forename: Robert
authors.initials: R
authors.lastname: Blouch
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: 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
chemical_list: 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