Silencing Genes to Prevent Infection

Electron Micrograph of Ebola Virus Particles

Ebola is a virus that causes a deadly hemorrhagic fever and is spread through contact with blood and contaminated needles. About 85 percent of the reported human cases of Ebola have resulted in death. The use of vaccines has protected monkeys, but are only effective when given prior to exposure to the virus. A team of scientists, including Thomas Gesibert, was initially attempting to boost host immunity for people exposed to the virus, but later turned to muting the virus's genes. This would at least buy time for other treatments, including the vaccine, to start working.


Gene silencing, or RNA interference (RNAi) occurs naturally. Some portions of DNA are transcribed into RNA, which are then translated into proteins that keep our cells functioning. However, there are other stretches of DNA that are transcribed into siRNA, or small interfering RNA, that is not translated into proteins. Instead of being translated into protein, these RNA strands are bound to portions of other RNA strands that have complementary sequences. This prevents the RNA from being translated into proteins and offers greater control over gene expression. Geisbert and his team attempted to artificially replicate this process to work on Ebola by creating siRNA that would bind to polymerase L, a gene that is vital for replication to occur.


The researchers were able to silence the gene and prevent replication effectively in cell culture studies, but encountered a new problem when testing the approach on animals infected with Ebola. "Naked" siRNA in blood and body tissues is broken done by enzymes. When the synthetic siRNA was injected into the test animals, the researchers needed to develop a "vehicle" that the infected cells would take up so that the siRNA contained within it would not be broken down by enzymes. The initial packaging system was ineffective, but Geiser then packaged the siRNA into SNALPs, or stable nucleic acid lipid particles. Cells like dendritic cells and macrophages are targeted by Ebola and were capable of taking up the SNALPs, resulting in a successful test with siRNA-containing SNALPs when used on guinea pigs.


When testing the approach on monkeys infected with Ebola, Geiser also included siRNAs to target viral genes that are thought to inhibit the immune system. They injected the SNALPs containing the siRNAs into the monkeys 30 minutes after injecting Ebola and injected the SNALPs every day for a week as well. After seven days, all of the monkeys were virus-free. Gesier hopes to push his approach to work on people infected by Ebola up to 24 hours after infection.


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