In a world full of scary viruses, Ebola surely ranks right up there amongst the scariest. It can cause fever, rashes, muscle pain, headache, followed by internal and external bleeding, 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 to combat the virus. Now scientists report they have successfully prevented monkeys exposed to the virus from dying from hemorrhagic fever and suggest that such protection should be possible for humans.
To interfere with the replication process of the virus the scientists used tiny particles of genetic material called small interfering RNAs (siRNAs) to target 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.
Previous research showed that the SNALP-RNAi therapeutic used in the study completely protected guinea pigs when administered shortly after a lethal dose of ZEBOV was administered. However, this new 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.
The researchers say that further studies in monkeys would be necessary to refine dosing, toxicology and other issued before the treatment could be licensed for human use and that the process has applications for viruses other than Ebola.
"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 titled, “Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept 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. It is published in medical journal The Lancet.
