US scientists have discovered two compounds from a family known as antisense phosphorodiamidate morpholino oligomers, or PMOs, can protect monkeys infected with Ebola and Marburg viruses from going on to develop lethal hemorrhagic fever, which has a 90 per cent fatality rate in humans; and they are now proceeding with clinical trials.

The "proof of concept" study that led to these findings was a collaboration between the US Army Medical Research Institute of Infectious Diseases (USAMRIID) based at Fort Detrick, Maryland, and AVI BioPharma, a Washington-based biotechnology firm, and was published in the 22 August advanced online issue of Nature Medicine.

There are currently no vaccines or effective treatments for the Ebola and Marburg filoviruses, which are commonly transmitted through blood and bodily fluids. However, infection can also occur via the aerosol route, which is why they are a cause of grave concern as potential weapons in biological warfare or terrorism.

When scientists research these viruses they have to work in special maximum containment labs and follow Biosafety level 4 procedures where they have to wear positive-pressure biohazard suits and breathe filtered air.

In their paper, first author Travis K. Warren of USAMRIID and colleagues describe how one PMO compound AVI-6002, from a group they called PMOplus (short for positively charged phosphorodiamidate morpholino oligomers), protected 60 per cent of monkeys infected with the Ebola virus and another called AVI-6003 protected 100 per cent of monkeys infected with Marburg.

Moreover, they showed that the PMOplus compounds protected the monkeys even when they were given one hour after exposure to the viruses, suggesting they could be used to treat people who accidentally become infected in labs and hospitals.

Warren said in a statement that the compounds block critical genetic viral sequences, halting virus replication long enough to give the host immune system time to mount a defence and eliminate it from the body.

To begin with, Warren and colleagues tested various PMO compounds on mice and guinea pigs infected with Ebola, until they found one called AVI-6002 that resulted in a survival rate of 90 per cent and over in animals treated either before or just after exposure.

They then proceeded to prove the concept in a series of studies on monkeys. First they exposed 9 monkeys to Ebola virus and gave 8 of them AVI-6002 within half to one hour later. 5 of the 8 survived. In a second set of experiments, 3 of 5 monkeys in each group survived when given a dose of 40 mg of AVI-6002 per kg of body weight.

Warren and colleagues then turned to the Marburg virus (more specifically the Lake Victoria Marburg virus, MARV): as before, they screened potential candidate compounds in mice and guinea pigs, until they found AVI-6003, which was more than 90 per cent effective at preventing Marburg infection in both animals.

In a further set of experiments on cynomolgus monkeys (crab eating macaques), they showed that AVI-6003 was 100 per cent effective, if given 30 to 60 minutes after infection with a dose of 40 mg per kg body weight.

They concluded that:

"PMOplus may be useful for treating these [Ebola and Marburg] and other highly pathogenic viruses in humans."

The reason the USAMRIID and AVI BioPharma team set out to investigate these compounds in the first place was because in February 2004, a USAMRIID scientist accidentally stuck her thumb with a needle while treating Ebola-infected mice.

The researcher went into quarantine following recommendation by USAMRIID medical experts that she be isolated for 21 days to check if she had been infected.

The unfortunate incident coincided with a visit by Dr. Patrick Iversen from AVI BioPharma, and the company immediately volunteered to try and find compounds to treat her if she should need it.

The team at AVI worked four days solid to develop human-grade anti-Ebola compounds, and in the meantime a team of experts from AVI and USAMRIID put together a request to seek emergency approval from the US Food and Drug Administration (FDA) to use the experimental drugs if necessary.

Five days after the exposure the compounds were in the hands of the USAMRIID medical team.

However, the scientist was luckily not infected and the drugs did not have to be used. But the two organizations decided to press ahead and test them on animals, and that is how these studies got off the ground.

USAMRIID commander Colonel John P Skvorak told the press that:

"This report of successful early post-exposure treatment of filovirus hemorrhagic fever is significant on its own."

"But the drug characteristics of these PMOs also support investigation of potentially broader therapeutic applications," he added.

The researchers have submitted investigational new drug applications (IND) for AVI-6002 and AVI-6003 to the US Food and Drug Administration (FDA) and are proceeding with clinical trials.

"Advanced antisense therapies for postexposure protection against lethal filovirus infections."
Travis K Warren, Kelly L Warfield, Jay Wells, Dana L Swenson, Kelly S Donner, Sean A Van Tongeren, Nicole L Garza, Lian Dong, Dan V Mourich, Stacy Crumley, Donald K Nichols, Patrick L Iversen & Sina Bavari.
Nature Medicine, Published online: 22 August 2010.
DOI:10.1038/nm.2202

Additional source: USAMRIID.

: Catharine Paddock, PhD

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