Update: RNAi Based Treatments for Ebola

PMI Backbone Structure (Credit: AVI BioPharma)
PMO Backbone Structure (Credit: AVI BioPharma)
Another RNAi based treatment for Ebola has been developed. Researchers at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) found that >60% of monkeys given a lethal dose of Zaire Ebola virus survived after treatment with AVI-6002, a targeted, positively charged, anti-sense phosphorodiamidate morpholino oligomers (PMO) developed by AVI BioPharma . Another targeted PMO, AVI-6003, was able to protect 100% of monkeys from a lethal dose of Lake Victoria Marburg virus. Both drugs were given daily for either 10 or 14 days. Both the Zaire Ebola virus and Lake Victoria Marburg virus are filoviruses that can cause deadly hemorrhagic fevers and are potential biological weapons agents.

As explained before, viral RNAi treatments consist of small pieces of RNA, siRNA, that bind and block specific viral RNA sequences.  This prevents the viral RNA from being translated into a protein or preforming another task which may be necessary to a virus’s survival.  Because siRNA is stable for only a short amount of time inside or outside of the body, the researchers from the above study utilized PMOs, which are more stable siRNA analogs.


PMO (morpholino) & RNA Heteroduplex Structure: Notice that the base pairs (A, T, U, G, C) are the same, allowing an anti-sense PMO to bind a sense strand of RNA.
The drugs AVI-6002 and AVI-6003 use PMOplus technology from AVI BioPharma and have positively charged backbones (PMOs do not normally carry a charge). This helps them enter host cells and also to tightly bind its target viral RNA (which has a negatively charged phophodiester backbone), even if a mutation has occured in the viral RNA. These treatments will be entering phase I clinical trials.

The Tekmira Pharmaceutical Corporation already stabilized siRNA for delivery by enveloping it within a lipid capsule, termed a “stable nucleic acid-lipid particle” or SNALP. Their SNALP RNAi based treatment tested at USAMRIID for the Zaire Ebola virus saved 4 of 4 monkeys when the treatment was given 7 times over 7 days.  2 of 3 monkeys survived with just 4 treatments in another study.  This treatment method is still in pre-clinical trials.

Dosage and Suggested Studies
The PMO based RNAi treatment study used 40mg/kg of PMO (an siRNA analog), whereas the SNALP based RNAi treatment study used only 2mg/kg of siRNA. This is likely because the SNALP readily fuses with cell membranes to deliver the siRNA, whereas only a small portion of the total PMOs given would be actively taken up by the target cell. It would be interesting to test the effectiveness of these two RNAi treatments together, using the SNALP to effectively deliver specific PMO sequences to the inside of an infected cell.

Somewhat ironically, the RNAi methods used to treat both Ebola and Marburg viruses are dual use, and could be used to weaken the immune system.

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