Journal Article

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

Mire, Chad E., Geisbert, Thomas W., Lee, Amy C. H., Fenton, Karla A., Zhou, Joy Z., Geisbert, Joan B., Barnard, Trisha R., MacLachlan, Ian, Thi, Emily P., Snead, Nicholas M., Deer, Daniel J., Agans, Krystle N.

2015

Overview

Ebola-virus-targeting short interfering RNAs (siRNAs) encapsulated in lipid nanoparticles are adapted to the current outbreak strain of the virus, and the siRNA cocktail is shown to protect nonhuman primates fully when administered 3 days after challenge with the current West African Ebola virus isolate; upon viral sequence data availability, the drug can be adapted to the new virus and produced in as little as 8 weeks. Treating the current Ebola outbreak Ebola virus-targeting siRNAs encapsulated in lipid nanoparticles (TKM-Ebola) have been shown previously to provide post-exposure protection of nonhuman primates against lethal Ebola virus challenge. The therapy has also been used on compassionate grounds in a number of human patients in the current outbreak, although the efficacy in humans is not known. Here, Thomas Geisbert and colleagues rapidly adapt the TKM-Ebola cocktail to the current outbreak strain of the virus and show that it is able to fully protect nonhuman primates when administered 3 days after challenge with the current West African EBOV isolate. Once viral sequence data becomes available, the drug can be adapted to the new virus and produced in as little as 8 weeks. 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 controlled 1 . Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States 2 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/596/2042 / Animals / Base Sequence / Care and treatment / Disease Models, Animal / Ebola hemorrhagic fever / Ebola virus / Ebolavirus - classification / Ebolavirus - drug effects / Ebolavirus - genetics / Female / Hemorrhagic Fever, Ebola - pathology / Hemorrhagic Fever, Ebola - prevention & control / Hemorrhagic Fever, Ebola - therapy / Hemorrhagic Fever, Ebola - virology / Humanities and Social Sciences / Humans / letter / Macaca mulatta - virology / Male / Medical treatment / multidisciplinary / Nanoparticles - administration & dosage / Outbreaks / Physiological aspects / Primates / Ribonucleic acid / RNA / RNA, Small Interfering - administration & dosage / RNA, Small Interfering - pharmacology / RNA, Small Interfering - therapeutic use / Science / Survival Analysis / Time Factors / Treatment Outcome / Viral Load - drug effects