A cure for Ebola?


There are few infectious diseases as violent and as lethal as the Ebola Haemorragic Fever.  This terrible disease was first described in 1976 at a mission hospital at the Ebola river in Zaire (now the Democratic Republic of Congo).  The disease is 80% fatal, the victims die painfully from a literal meltdown of their organs. Because the disease is transmitted via direct contact with bodily fluids, and because it is relatively non-infectious during the incubation period, it does not spread as well as airborne agents, such as the flu virus.  Outbreaks are relatively short and contained, and there hasn’t been an Ebola pandemic. The different Ebola virus strains are classified as Grade A bioterror weapons: although not spread by aerosol, the viral particles can still be inhaled, and the violence and rapid spread and lack of cure for the disease are worrying. Ebola is lethal in other primates too, besides humans. A  study from 2006 claims that Ebola may have killed up to 5,000 gorillas.

Yesterday, a report was published in The Lancet that may hail a cure for the disease, and provide hope for a treatment for many other viral diseases.  The researchers infected seven Macaque and Rhesus monkeys with the lethal Zaire Ebola Virus, and then injected them with synthetic RNA that specifically targets the virus. All but one of the infected monkeys survived and fully recovered.

Transmission Electron Micrograph of the Ebola Virus. Credit: US Center for Disease Control

The interesting bit about the cure is how it works. The researchers used small interfering RNA or siRNA. siRNA is a natural mechanism in plants and animals that interferes with the expression of specific RNA and causes its destruction in the cell. siRNA molecules are short  (21-23bp long) RNA molecules by themselves. They block other RNA molecules very specifically, without disrupting the whole cell.  Think of a military censor that blacks out only very specific words in soldier’s letters, those that may cause damage if taken any further, but leaves in the benign stuff.  (OK, that was before email, I am not even sure there are military censors now.) It is a form of control of RNA expression in the cell, but it is also used to interfere with the expression of harmful alien RNA, such as viral RNA: viruses operate by hijacking the cellular machinery to make their own RNA and proteins, which is the reason why some of them cause diseases.  Now, siRNA can also be synthesized in the lab and delivered intravenously using lipid capsules. The capsules are delivered via the vascular systems to the infected cells, deliver the siRNA into the cells and block the virus from making its own RNA. If done right, the synthetic siRNA blocks only the viral RNA, leaving the cellular RNA alone. Here the researchers targeted the RNA that codes for the viral polymerase protein: the very protein that the virus uses to make its own proteins. So no polymerase RNA –> no polymerase protein –> no Ebola making factory. More than that, this is the first time that siRNA treatment has been shown to work in primate models of a human disease. So what we have here is a new class of antiviral drugs, that may be used against other diseases.

I seriously doubt we will see controlled human trials before the next natural outbreak, so this is as close as we can get to a proven treatment for Ebola. Finally, here is a short clip showing how siRNA works in the cell. Here the siRNA is injected, rather than delivered using lipid capsules, but the rest remains the same.

“Small interfering RNAs (siRNAs) are 2123nt dsRNA (double-stranded RNA) molecules that facilitate potent and sequence-specific gene suppression via the mechanism of RNAi (RNA interference). siRNA pathway animation gives an idea on the mechanism of gene supression by siRNA. When introduced into cultured mammalian cells, siRNAs facilitate the degradation of mRNA sequences to which they are homologous; thereby silencing the encoding gene. The basic mechanism behind RNAi is the breaking of a dsRNA matching a specific gene sequence into short pieces of siRNA. These siRNAs post-transcriptionally silences a gene through mRNA degradation. mRNA silencing involves the chopping of long dsRNA into smaller pieces, corresponding to both sense and antisense strands of the target gene by the Rnase-III (Ribonuclease-III) family member, Dicer. Dicer chops dsRNA into two classes of smaller RNAs—miRNAs (microRNAs) and siRNAs. Dicer delivers these siRNAs to a group of proteins called the RISC (RNA-Inducing Silencing Complex), which uses the antisense strand of the siRNA to bind to and degrade the corresponding mRNA, resulting in gene silencing. siRNAs are associated with silencing triggered by transgenes, microinjected RNA, viruses, and transposons, and hence can be considered intermediaries in host defense pathways against foreign nucleic”

(From the caption of the Protein Lounge video http://www.proteinlounge.com)

Prof Thomas W Geisbert Corresponding Amy CH 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 (2010). Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study The Lancet, 375 (9729), 1896-1905 : doi:10.1016/S0140-6736(10)60357-1

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