Marburg virus infection in nonhuman primates: Therapeutic treatment by lipid-encapsulated siRNA.
Emily P Thi, Chad E Mire, Raul Ursic-Bedoya, Joan B Geisbert, Amy C H Lee, Krystle N Agans, Marjorie Robbins, Daniel J Deer, Karla A Fenton, Ian MacLachlan, Thomas W Geisbert
Author Information
Emily P Thi: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
Chad E Mire: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Raul Ursic-Bedoya: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
Joan B Geisbert: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Amy C H Lee: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
Krystle N Agans: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Marjorie Robbins: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
Daniel J Deer: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Karla A Fenton: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Ian MacLachlan: Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada.
Thomas W Geisbert: Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA.
Marburg virus (MARV) and the closely related filovirus Ebola virus cause severe and often fatal hemorrhagic fever (HF) in humans and nonhuman primates with mortality rates up to 90%. There are no vaccines or drugs approved for human use, and no postexposure treatment has completely protected nonhuman primates against MARV-Angola, the strain associated with the highest rate of mortality in naturally occurring human outbreaks. Studies performed with other MARV strains assessed candidate treatments at times shortly after virus exposure, before signs of disease are detectable. We assessed the efficacy of lipid nanoparticle (LNP) delivery of anti-MARV nucleoprotein (NP)-targeting small interfering RNA (siRNA) at several time points after virus exposure, including after the onset of detectable disease in a uniformly lethal nonhuman primate model of MARV-Angola HF. Twenty-one rhesus monkeys were challenged with a lethal dose of MARV-Angola. Sixteen of these animals were treated with LNP containing anti-MARV NP siRNA beginning at 30 to 45 min, 1 day, 2 days, or 3 days after virus challenge. All 16 macaques that received LNP-encapsulated anti-MARV NP siRNA survived infection, whereas the untreated or mock-treated control subjects succumbed to disease between days 7 and 9 after infection. These results represent the successful demonstration of therapeutic anti-MARV-Angola efficacy in nonhuman primates and highlight the substantial impact of an LNP-delivered siRNA therapeutic as a countermeasure against this highly lethal human disease.
