Advanced antisense therapies for postexposure protection against lethal filovirus infections

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Abstract

Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30–60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.

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Figure 1: Postexposure protection of ZEBOV-infected rhesus monkeys by AVI-6002.
Figure 2: Postexposure protection of MARV-infected cynomolgus monkeys by AVI-6003.

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Acknowledgements

We thank C. Rice, D. Reed, N. Posten and J. Stockman for technical assistance and M. Ait Ichou and J. Hardick for their help in the initial viral quantification studies. S. Norris and D. Fisher provided statistical assistance and conducted animal randomization procedures. L. Welch, S. Bradfute, R. Panchal and J. Kuhn provided support and discussions and critically reviewed the manuscript. These studies were supported by the US Defense Threat Reduction Agency awarded to AVI BioPharma (HDTRA1-07-C-010) and S.B. (4.10022-08-RD-B and TMTI0048-09-RD-T). Disclaimer: the opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army.

Author information

T.K.W. designed and supervised multiple-dose primate evaluations, evaluated results and wrote the manuscript. K.L.W. designed, supervised and conducted proof-of-concept nonhuman primate and rodent investigations and evaluated results. J.W., D.L.S., K.S.D., S.A.V.T. and N.L.G. conducted the nonhuman primate and rodent studies and analyzed samples. L.D. conducted quantitative PCR analysis. D.K.N. conducted post-mortem analyses of all nonhuman primate subjects. D.V.M. and S.C. were responsible for synthesis of PMOplus agents. P.L.I. and S.B. designed experiments, evaluated results and provided project oversight. All authors read and approved the final version of the manuscript.

Correspondence to Patrick L Iversen or Sina Bavari.

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Competing interests

P.L.I. and S.B. claim intellectual property regaring PMOplus technologies for treatment of viral infections. P.L.I., D.V.M. and S.C. are employees of AVI BioPharma.

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Supplementary Figures 1 and 2, Supplementary Tables 1–3 and Supplementary Methods (PDF 295 kb)

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