Volume 375, Issue 9729, Pages (May 2010)

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Presentation transcript:

Volume 375, Issue 9729, Pages 1896-1905 (May 2010) Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study Prof Thomas W Geisbert, PhD, Amy CH Lee, MSc, Marjorie Robbins, PhD, Joan B Geisbert, Anna N Honko, PhD, Vandana Sood, MSc, Joshua C Johnson, BSc, Susan de Jong, PhD, Iran Tavakoli, BSc, Adam Judge, PhD, Lisa E Hensley, PhD, Ian MacLachlan, PhD The Lancet Volume 375, Issue 9729, Pages 1896-1905 (May 2010) DOI: 10.1016/S0140-6736(10)60357-1 Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 1 Effect of small interfering RNAs (siRNAs) targeting virion protein genes VP24 (A) and VP35 (B) of Zaire Ebola virus (ZEBOV) expressed in a non-viral plasmid-based system in HepG2 cells Error bars represent SD of triplicate tissue culture wells. The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 2 Effect of small interfering RNAs (siRNAs) on synthesis of interleukin 6 (A) and interferon α (B), induction of interferon-induced protein with tetratricopeptide repeats (IFIT1) mRNA in mice (C), and induction of interferon α in human peripheral blood mononuclear cell cultures (D) Data are mean (SD). Error bars represent SD. Luc=luciferase. PBS=phosphate-buffered saline. Luc mod=modified luciferase. GAPDH=glyceraldehyde 3-phosphate dehydrogenase. The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 3 Rapid amplification of cDNA ends (RACE)-PCR of small interfering RNA (siRNA)-mediated cleavage of Zaire Ebola virus (ZEBOV) L polymerase, virion protein (VP) 24 (VP24), and VP35 mRNAs in ZEBOV-infected Vero E6 cells Vero E6 cells were treated with stable nucleic acid-lipid particles (SNALPs) containing ZEBOV siRNA cocktail, modified luciferase (Luc mod), or phosphate-buffered saline (PBS). (B) Vero E6 cells were treated with SNALPs containing EK-1-mod, VP24-1160-mod, VP35-855-mod, ZEBOV siRNA cocktail, Luc mod, or PBS. The order of samples for each RACE PCR shown in the gel is SNALPs containing PBS, single gene-specific siRNAs (EK-1-mod, VP24-1160-mod, or VP35-855-mod), ZEBOV cocktail, and Luc mod. Lanes 1 and 17 are the 100 base pair (bp) ladder, lanes 2–5 are EK-1 RACE PCR, lanes 7–10 are VP24-1160 RACE, and lanes 12–15 are VP35-855 RACE. Lanes 6, 11, and 16 are empty. The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 4 Proportion of differentiated cells with uptake of stable nucleic acid-lipid particles (SNALPs) containing fluorescein-isothiocyanate-labelled modified luciferase small interfering RNAs The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 5 Effect of daily administration of stable nucleic acid-lipid particles (SNALPs) containing Zaire Ebola virus (ZEBOV) small interfering RNAs on activities (siRNAs) of alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase (A), and blood cell counts (B) in mice PBS=phosphate-buffered saline. The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions

Figure 6 Survival curves for Zaire Ebola virus (ZEBOV)-infected rhesus macaques treated after challenge with stable nucleic acid-lipid particles containing ZEBOV small interfering RNAs Study 1: four postexposure treatments. Study 2: seven post exposure treatments. The Lancet 2010 375, 1896-1905DOI: (10.1016/S0140-6736(10)60357-1) Copyright © 2010 Elsevier Ltd Terms and Conditions