title: Protection against lethal Marburg virus infection mediated by lipid encapsulated small interfering RNA.
abstract: BACKGROUND
  Marburg virus (MARV) infection causes severe morbidity and mortality in humans and nonhuman primates. Currently, there are no licensed therapeutics available for treating MARV infection. Here, we present the in vitro development and in vivo evaluation of lipid-encapsulated small interfering RNA (siRNA) as a potential therapeutic for the treatment of MARV infection.
  
  
  METHODS
  The activity of anti-MARV siRNAs was assessed using dual luciferase reporter assays followed by in vitro testing against live virus. Lead candidates were tested in lethal guinea pig models of 3 different MARV strains (Angola, Ci67, Ravn).
  
  
  RESULTS
  Treatment resulted in 60%-100% survival of guinea pigs infected with MARV. Although treatment with siRNA targeting other MARV messenger RNA (mRNA) had a beneficial effect, targeting the MARV NP mRNA resulted in the highest survival rates. NP-718m siRNA in lipid nanoparticles provided 100% protection against MARV strains Angola and Ci67, and 60% against Ravn. A cocktail containing NP-718m and NP-143m provided 100% protection against MARV Ravn.
  
  
  CONCLUSIONS
  These data show protective efficacy against the most pathogenic Angola strain of MARV. Further development of the lipid nanoparticle technology has the potential to yield effective treatments for MARV infection.
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada.
authors.forename: Raul
authors.initials: R
authors.lastname: Ursic-Bedoya
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robbins
authors.forename: Joan B
authors.initials: JB
authors.lastname: Geisbert
authors.forename: Adam
authors.initials: A
authors.lastname: Judge
authors.forename: Ian
authors.initials: I
authors.lastname: MacLachlan
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D005814:Genes, Viral; D006168:Guinea Pigs; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008379:Marburg Virus Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D029024:Marburgvirus / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D016601:RNA-Binding Proteins; D016019:Survival Analysis; D019562:Viral Load
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016207:Cytokines; D004337:Drug Carriers; C092573:Ifit1 protein, mouse; D008055:Lipids; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
keywords: LNP; Marburg virus; RNAi; filovirus; guinea pig; siRNA; therapeutics; treatment