A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection

Travis K. Warren, Chris A. Whitehouse, Jay Wells, Lisa Welch, Alison E. Heald, Jay S. Charleston, Pete Sazani, St Patrick Reid, Patrick L. Iversen, Sina Bavari

Research output: Contribution to journalArticle

41 Citations (Scopus)

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. IMPORTANCE 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.

Original languageEnglish (US)
Article numbere02344
JournalmBio
Volume6
Issue number1
DOIs
StatePublished - Feb 10 2015

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Ebola Hemorrhagic Fever
Ebolavirus
Morpholinos
Macaca mulatta
Primates
Disease Outbreaks
Geographic Locations
Messenger RNA
Western Africa
Virulence Factors
Virulence
Proteins
Vaccines

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Warren, T. K., Whitehouse, C. A., Wells, J., Welch, L., Heald, A. E., Charleston, J. S., ... Bavari, S. (2015). A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection. mBio, 6(1), [e02344]. https://doi.org/10.1128/mBio.02344-14

A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection. / Warren, Travis K.; Whitehouse, Chris A.; Wells, Jay; Welch, Lisa; Heald, Alison E.; Charleston, Jay S.; Sazani, Pete; Reid, St Patrick; Iversen, Patrick L.; Bavari, Sina.

In: mBio, Vol. 6, No. 1, e02344, 10.02.2015.

Research output: Contribution to journalArticle

Warren, TK, Whitehouse, CA, Wells, J, Welch, L, Heald, AE, Charleston, JS, Sazani, P, Reid, SP, Iversen, PL & Bavari, S 2015, 'A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection', mBio, vol. 6, no. 1, e02344. https://doi.org/10.1128/mBio.02344-14
Warren, Travis K. ; Whitehouse, Chris A. ; Wells, Jay ; Welch, Lisa ; Heald, Alison E. ; Charleston, Jay S. ; Sazani, Pete ; Reid, St Patrick ; Iversen, Patrick L. ; Bavari, Sina. / A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection. In: mBio. 2015 ; Vol. 6, No. 1.
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