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

Emily P. Thi, Amy C H Lee, Joan B. Geisbert, Raul Ursic-Bedoya, Krystle N. Agans, Marjorie Robbins, Daniel J. Deer, Karla A. Fenton, Andrew S. Kondratowicz, Ian MacLachlan, Thomas Geisbert, Chad Mire

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18 Scopus citations

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 5days 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 log 10 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.

Original languageEnglish (US)
Article number16142
JournalNature Microbiology
Volume1
DOIs
StatePublished - Aug 22 2016

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology
  • Immunology
  • Microbiology (medical)
  • Cell Biology
  • Genetics

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    Thi, E. P., Lee, A. C. H., Geisbert, J. B., Ursic-Bedoya, R., Agans, K. N., Robbins, M., Deer, D. J., Fenton, K. A., Kondratowicz, A. S., MacLachlan, I., Geisbert, T., & Mire, C. (2016). Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA. Nature Microbiology, 1, [16142]. https://doi.org/10.1038/nmicrobiol.2016.142