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Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates

Nature volume 521, pages 362365 (21 May 2015) | Download Citation

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Abstract

The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled1. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States2. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

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Acknowledgements

We thank V. Borisevich for assistance with clinical pathology assays performed in the GNL BSL-4 laboratory. We also thank S. Klassen for his assistance with siRNA-LNP preparation. This study was supported by the Department of Health and Human Services, National Institutes of Health grant U19AI109711 to T.W.G. and I.M.

Author information

Author notes

    • Emily P. Thi
    •  & Chad E. Mire

    These authors contributed equally to this work.

Affiliations

  1. Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada

    • Emily P. Thi
    • , Amy C. H. Lee
    • , Joy Z. Zhou
    • , Nicholas M. Snead
    • , Trisha R. Barnard
    •  & Ian MacLachlan
  2. Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA

    • Chad E. Mire
    • , Joan B. Geisbert
    • , Krystle N. Agans
    • , Daniel J. Deer
    • , Karla A. Fenton
    •  & Thomas W. Geisbert
  3. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA

    • Chad E. Mire
    • , Joan B. Geisbert
    • , Krystle N. Agans
    • , Daniel J. Deer
    • , Karla A. Fenton
    •  & Thomas W. Geisbert

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Contributions

E.P.T. and J.Z.Z. designed the siRNA and did preparative work for dual luciferase reporter studies. E.P.T., N.M.S., J.Z.Z. and A.C.H.L. designed the dual luciferase reporter studies. J.Z.Z., T.R.B. and N.M.S. conducted the dual luciferase reporter studies and analysed the data. E.P.T., C.E.M., A.C.H.L., I.M. and T.W.G. conceived and designed the NHP study. C.E.M., J.B.G., D.J.D. and T.W.G. performed the NHP challenge and treatment experiments and conducted clinical observations of the animals. J.B.G., K.N.A. and D.J.D. performed the clinical pathology assays. J.B.G. performed the EBOV Makona infectivity assays. C.E.M. and K.N.A. performed the PCR assays. E.P.T., C.E.M., J.B.G., K.N.A., D.J.D., K.A.F., A.C.H.L., I.M. and T.W.G. analysed the data. K.A.F. performed histological and immunohistochemical analysis of the data. E.P.T., C.E.M., A.C.H.L. and T.W.G. wrote the paper. All authors had access to all of the data and approved the final version of the manuscript.

Competing interests

A.C.H.L., I.M. and T.W.G. claim intellectual property regarding RNA interference for the treatment of filovirus infections. I.M. and T.W.G. are co-inventors on US Patent 7,838,658 ‘siRNA silencing of filovirus gene expression’ and A.C.H.L., I.M. and T.W.G. are co-inventors on US Patent 8,716,464 ‘Compositions and methods for silencing Ebola virus gene expression’.

Corresponding author

Correspondence to Thomas W. Geisbert.

Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the University of Texas Medical Branch.

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DOI

https://doi.org/10.1038/nature14442

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