title: Marburg virus infection in nonhuman primates: Therapeutic treatment by lipid-encapsulated siRNA.
abstract: Marburg virus (MARV) and the closely related filovirus Ebola virus cause severe and often fatal hemorrhagic fever (HF) in humans and nonhuman primates with mortality rates up to 90%. There are no vaccines or drugs approved for human use, and no postexposure treatment has completely protected nonhuman primates against MARV-Angola, the strain associated with the highest rate of mortality in naturally occurring human outbreaks. Studies performed with other MARV strains assessed candidate treatments at times shortly after virus exposure, before signs of disease are detectable. We assessed the efficacy of lipid nanoparticle (LNP) delivery of anti-MARV nucleoprotein (NP)-targeting small interfering RNA (siRNA) at several time points after virus exposure, including after the onset of detectable disease in a uniformly lethal nonhuman primate model of MARV-Angola HF. Twenty-one rhesus monkeys were challenged with a lethal dose of MARV-Angola. Sixteen of these animals were treated with LNP containing anti-MARV NP siRNA beginning at 30 to 45 min, 1 day, 2 days, or 3 days after virus challenge. All 16 macaques that received LNP-encapsulated anti-MARV NP siRNA survived infection, whereas the untreated or mock-treated control subjects succumbed to disease between days 7 and 9 after infection. These results represent the successful demonstration of therapeutic anti-MARV-Angola efficacy in nonhuman primates and highlight the substantial impact of an LNP-delivered siRNA therapeutic 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: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Raul
authors.initials: R
authors.lastname: Ursic-Bedoya
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Geisbert
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Amy C H
authors.initials: ACH
authors.lastname: Lee
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Krystle N
authors.initials: KN
authors.lastname: Agans
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robbins
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deer
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 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: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D006801:Humans; D008055:Lipids / Q000627:therapeutic use*; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology*; D008379:Marburg Virus Disease / Q000473:pathology / Q000628:therapy / Q000821:virology*; D029024:Marburgvirus / Q000276:immunology / Q000502:physiology*; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D012367:RNA, Viral / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D014766:Viremia / Q000473:pathology
chemical_list: D000956:Antigens, Viral; D008055:Lipids; D034741:RNA, Small Interfering; D012367:RNA, Viral