"Over the past decade, we have evaluated numerous therapeutic approaches for the treatment of lethal viruses, such as Ebola," said co-author Dr. Lisa E. Hensley of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). "None of them have conferred complete protection to Ebola virus-infected primates—until now."
Using particles called small interfering RNAs (siRNAs), the authors targeted a protein (called the L protein) that is essential for Ebola virus replication. RNA inhibitors, as they are commonly called, are based on a natural gene silencing mechanism used by all cells, and RNAi therapeutics rely on a delivery technology to be effective.
Lipid nanoparticles (LNPs) are the most widely used siRNA delivery approaches. In this study, the research team used a proprietary technology called SNALP, or stable nucleic acid-lipid particles, to deliver the therapeutics to disease sites in animal models infected with the Zaire strain of Ebola virus (ZEBOV).
A group of three rhesus macaques was given anti-ZEBOV siRNAs intravenously, 30 minutes after exposure to the virus, and again on days 1, 3, and 5. A second group of four macaques was given the treatment after 30 minutes, and on days 1, 2, 3, 4, 5, and 6, after challenge with ZEBOV.
Two of the three animals in the first group (which received four post-exposure treatments) were protected from lethal ZEBOV infection and survived. All four of the monkeys given seven post-exposure treatments were protected. The treatment regimen in the second study was well tolerated, with minor changes in liver enzymes that might have been related to viral infection.
The study represents the first demonstration of complete protection against a lethal human infectious disease in nonhuman primates using RNAi, according to lead author Dr. Thomas W. Geisbert of the Boston University School of Medicine.
"We believe this work justifies the immediate development of Ebola SNALP as a countermeasure to treat Ebola infected patients, either in outbreaks or accidental laboratory exposures," he said.
Ebola virus causes hemorrhagic fever with case fatality rates as high as 80 percent in humans. The virus, which is infectious by aerosol (although more commonly spread through blood and bodily fluids of infected patients), is of concern both as a global health threat and a potential agent of biological warfare or terrorism.
Currently there are no available vaccines or therapies, so researchers working with Ebola virus must do so in maximum containment (Biosafety Level 4) laboratories. In these specially designed laboratories, investigators wear positive pressure "space suits" and breathe filtered air as they work, and all laboratory waste streams are sterilized.
The SNALP-RNAi therapeutic used in the study was developed by Tekmira Pharmaceuticals Corporation of Vancouver, BC. Previous research showed that these siRNAs completely protected guinea pigs when administered shortly after a lethal dose of ZEBOV was administered. While rodent studies are useful for screening prospective medical countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models.
Further studies in monkeys would be necessary to refine dosing, toxicology and other issued before the treatment could be licensed for human use.
"The significance of this report goes beyond the protection against Ebola virus," said COL John P. Skvorak, commander of USAMRIID. "It also represents the potential for this concept to be applied to other viral infections."
The study was a collaborative effort between USAMRIID, Boston University and Tekmira, and was partly funded by the Defense Threat Reduction Agency's Transformational Medical Technologies Initiative.
USAMRIID, located at Fort Detrick, Maryland, is the lead medical research laboratory for the U.S. Department of Defense Biological Defense Research Program, and plays a key role in national defense and in infectious disease research. The Institute conducts basic and applied research on biological threats resulting in medical solutions (such as vaccines, drugs and diagnostics) to protect the warfighter. While USAMRIID's primary mission is focused on the military, its research often has applications that benefit society as a whole. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command. For more information, visit www.usamriid.army.mil.
Reference: Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Thomas W. Geisbert, Amy C. H. Lee, Marjorie Robbins, Joan B. Geisbert, Anna N. Honko, Vandana Sood, Joshua C. Johnson, Susan de Jong, Iran Tavakoli, Adam Judge, Lisa E. Hensley, Ian MacLachlan. The Lancet: 29 May 2010; 375: 1896-190
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