title: Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques.
abstract: Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Whitehouse
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Jay
authors.initials: J
authors.lastname: Wells
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Welch
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Charleston
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Alison
authors.initials: A
authors.lastname: Heald
authors.affiliation: Pathology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Nichols
authors.affiliation: Pathology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Mattix
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Palacios
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kugleman
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008252:Macaca fascicularis / Q000821:virology; D008297:Male; D008379:Marburg Virus Disease / Q000628:therapy* / Q000821:virology; D029024:Marburgvirus / Q000235:genetics* / Q000502:physiology; D060172:Morpholinos / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism; D061665:Time-to-Treatment
chemical_list: C000599943:AVI-7288; D060172:Morpholinos; D016372:RNA, Antisense