title: A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal Ebola virus infection.
abstract: Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures.
  
  
  OBJECTIVE
  Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval.
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors: Travis K
authors: TK
authors: Warren
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors: Chris A
authors: CA
authors: Whitehouse
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors: Jay
authors: J
authors: Wells
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors: Lisa
authors: L
authors: Welch
authors: Alison E
authors: AE
authors: Heald
authors: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors: Jay S
authors: JS
authors: Charleston
authors: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors: Pete
authors: P
authors: Sazani
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors: St Patrick
authors: SP
authors: Reid
authors: Patrick L
authors: PL
authors: Iversen
authors: Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA sina.bavari.civ@mail.mil.
authors: Sina
authors: S
authors: Bavari
mesh_terms: D000818:Animals; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D008253:Macaca mulatta; D060172:Morpholinos / Q000008:administration & dosage*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D060172:Morpholinos; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins