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Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA

Nature Microbiology volume 1, Article number: 16142 (2016) | Download Citation

Abstract

Although significant progress has been made in developing therapeutics against Zaire ebolavirus, these therapies do not protect against other Ebola species such as Sudan ebolavirus (SUDV). Here, we describe an RNA interference therapeutic comprising siRNA targeting the SUDV VP35 gene encapsulated in lipid nanoparticle (LNP) technology with increased potency beyond formulations used in TKM-Ebola clinical trials. Twenty-five rhesus monkeys were challenged with a lethal dose of SUDV. Twenty animals received siRNA-LNP beginning at 1, 2, 3, 4 or 5 days post-challenge. VP35-targeting siRNA-LNP treatment resulted in up to 100% survival, even when initiated when fever, viraemia and disease signs were evident. Treatment effectively controlled viral replication, mediating up to 4 log10 reductions after dosing. Mirroring clinical findings, a correlation between high viral loads and fatal outcome was observed, emphasizing the importance of stratifying efficacy according to viral load. In summary, strong survival benefit and rapid control of SUDV replication by VP35-targeting LNP confirm its therapeutic potential in combatting this lethal disease.

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Acknowledgements

The authors thank V. Borisevich for assistance with clinical pathology assays performed in the GNL BSL-4 laboratory, J. Heyes and K. Lam for data comparing endogenous gene silencing potency across LNP formulations, and 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 no. U19AI109711 to T.W.G. and E.P.T., and UC7AI094660 for BSL-4 operations support of the Galveston National Laboratory.

Author information

Author notes

    • Thomas W. Geisbert
    •  & Chad E. Mire

    These authors contributed equally to this work.

Affiliations

  1. Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada

    • Emily P. Thi
    • , Amy C. H. Lee
    • , Raul Ursic-Bedoya
    • , Marjorie Robbins
    • , Andrew S. Kondratowicz
    •  & Ian MacLachlan
  2. Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA

    • Joan B. Geisbert
    • , Krystle N. Agans
    • , Daniel J. Deer
    • , Karla A. Fenton
    • , Thomas W. Geisbert
    •  & Chad E. Mire
  3. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA

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

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Contributions

R.U.-B. and M.R. designed the siRNA and R.U.-B. conducted the dual luciferase reporter studies. R.U.-B., C.E.M., M.R., I.M. and T.W.G. designed the in vitro infection study. K.N.A. and C.E.M. performed the in vitro infection study. E.P.T., C.E.M., A.C.H.L., I.M. and T.W.G. conceived and designed the NHP studies. 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 SUDV 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.S.K, A.C.H.L. 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.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.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’). The other authors declare no competing interests. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the University of Texas Medical Branch.

Corresponding author

Correspondence to Thomas W. Geisbert.

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DOI

https://doi.org/10.1038/nmicrobiol.2016.142

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