title: Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates.
abstract: The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Thi
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Amy C H
authors.initials: AC
authors.lastname: Lee
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Geisbert
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Joy Z
authors.initials: JZ
authors.lastname: Zhou
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Krystle N
authors.initials: KN
authors.lastname: Agans
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Snead
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deer
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Trisha R
authors.initials: TR
authors.lastname: Barnard
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Karla A
authors.initials: KA
authors.lastname: Fenton
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: MacLachlan
authors.affiliation: 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000473:pathology / Q000517:prevention & control / Q000628:therapy* / Q000821:virology*; D006801:Humans; D008253:Macaca mulatta / Q000821:virology; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering