For nearly 10 years, researchers with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) have been collaborating with Sarepta Therapeutics, Inc., to develop an effective therapeutic agent against Ebola virus and other related viruses, called filoviruses.
When they started, cases of Ebola virus occurred sporadically and affected at most a few hundred people, usually in Africa. Most research focused on developing a product for a biodefense scenario, like if a terrorist group released Ebola virus in a certain population. “The idea that we would have cases of Ebola virus being diagnosed in the U.S. was on just a few people’s radar and was considered a remote possibility,” says Travis K. Warren, PhD, a principal investigator in the Molecular and Translational Sciences Division at the research institute at Fort Detrick, Md.
Now, with Ebola virus rampant in three West African countries, the work of investigators at USAMRIID has taken on added meaning. Despite many efforts to develop vaccines and antiviral medicines against filoviruses like Ebola, there are currently no licensed medical countermeasures against these viruses. Surprisingly, many products being used by doctors to treat patients infected with Ebola virus in West Africa have not been tested in any animal model or in non-human primates, Warren said.
In mBio this week, Warren and colleagues in the Army and at Sarepta published work showing that the experimental medication AVI-7537, which targets the gene coding for a protein in Ebola virus called VP24, protects 75% of Ebola virus-infected monkeys.
Their research compared drugs called phosphorodiamidate morpholino oligomers (PMOs) --- synthetic “antisense” molecules that target mRNAs within Ebola virus in a sequence-specific fashion and suppress translation. While previous work by the authors showed that a combination PMO targeting the genes that code for VP24 and another protein, VP35, protected rhesus monkeys from Ebola virus infection, the current study revealed that targeting VP24 alone was sufficient to confer protection from Ebola virus. Treatments consisting of placebo or an agenttargeting VP35 alone resulted in no protection (0% survival).
The majority of monkeys treated with AVI-7537 survived Ebola virus infection and showed substantial reduction of virus in their bloodstreams within eight days of treatment, compared to animals receiving a placebo (saline).
“This study demonstrates that we can protect non-human primates from Ebola virus, using only a single antisense agent,” says Warren, lead study author. “It also suggests that VP24 may be a key virulence factor encoded by Ebola virus, and is a promising target for the development of effective anti-Ebola virus countermeasures.”
During the study, researchers gave Ebola virus-infected rhesus monkeys one of three medications: AVI-7537; AVI-7539, which targets VP35; or a combination treatment that included both AVI-7537 and AVI-7539, called AVI-6002. A fourth group of monkeys received just saline and served as the control group. The animals received these treatments intravenously, once a day for up to 14 days.
Seventy-five percent of animals treated with AVI-7537 and 62 percent of animals receiving the combination treatment, AVI-6002, survived until the end of the study. By contrast, all animals receiving saline or AVI-7539 developed progressive signs of Ebola disease and succumbed.
Additional tests showed that AVI-6002 and AVI-7537 were similar in their ability to reduce viral load, substantially reducing or eliminating infectious virus and viral RNA in the animals’ bloodstreams. Animals treated with AVI-6002 and AVI-7537 also had less liver and kidney damage, a common complication of filovirus infection, than those treated with placebo or AVI-7539.
“The work demonstrates that impairment of VP24 alone is enough to protect against Ebola virus infection and that targeting VP24 may lead to the development of more effective countermeasures against this important viral pathogen,” said senior study author Sina Bavari, PhD, Science Director for the U.S. Army Medical Research Institute of Infectious Diseases.
Phase Ia clinical trials were successfully completed with AVI-7537; the product was well tolerated in healthy human volunteers. Continued development of this product is dependent on continued funding, Bavari said. Additional studies are pending.
-- Karen Blum