Researchers have demonstrated the use of a mini-genome system as a quick screening method to evaluate candidate drugs that could inhibit the Ebola virus. The method and technology can be performed in most standard labs and allows evaluation of two and three drug combinations.
Their results, published today in PLOS Neglected Tropical Diseases, provide details on the procedure for evaluating candidate anti-Ebola drugs and comparing the antiviral effectiveness of eight drugs from three different drug classes.
Interferons and anti-HIV drugs showed antiviral activity against the Ebola virus in their studies. The team was led by Dr. Eleanor Fish, senior scientist in the Toronto General Research Institute (TGRI) and Dr. Donald Branch, senior scientist in the Centre for Innovation – Canadian Blood Services and TGRI. Other collaborators were from the National Microbiology Laboratory in Winnipeg and the U.S. National Institutes of Health.
Research on new Ebola therapies has been limited by an inability to compare antiviral effectiveness, since cell model systems, treatment regimens and results are so varied that it is difficult to compare effectiveness amongst the compounds, and prioritize which ones are most promising to pursue.
“During this recent Ebola outbreak it became clear that many different experimental drugs were being considered, yet studies to evaluate the effectiveness of candidate drugs are hampered by the limited availability of appropriate safety level labs around the world and the difficulty of comparing results when different model systems were being used,” said Dr. Fish.
“We tested combinations because lower doses of each drug can be used, potentially decreasing side effects,” said Dr. Fish, a Professor in the Department of Immunology at the University of Toronto. “Using this technology, scientists will be able to measure the inhibitory effects of their experimental drugs on the replication of Ebola virus, allowing us to compare results with confidence. This approach will also decrease the possibility of the emergence of drug resistance.”
The viral mini-genome generated modifies the Ebola virus to produce virus-like particles that are no longer harmful to humans. The researchers were therefore able to do their work in a biosafety Level 2 Laboratory, which only requires some enhanced measures such as gloves and biological safety cabinets.
Using human cells and this model infection system, the researchers compared how well eight different drugs, in different combinations, at different doses and at times post-exposure, were able to inhibit the virus. Interferon beta, the most potent inhibitor of Ebola which the team identified as a result of the screening, is now part of a clinical trial of individuals who were infected with Ebola during the recent outbreak in Guinea.
“It was found that drugs normally used to treat HIV/AIDS were also effective at inhibiting Ebola, alone, but more so in combination with interferon beta,” noted Dr. Branch, who is also an Associate Professor, Medicine and Laboratory Medicine and Pathobiology, University of Toronto.
As of December 20th 2015, 28,637 cases and 11,315 deaths from Ebola have been reported worldwide, the vast majority of them in West Africa. The high mortality rate of the disease, estimated at around 60% in the most recent outbreak, made it one of the most deadly infectious diseases in the world. The World Health Organization (WHO) declared the outbreak in 2014-15 a public health emergency of international concern and it is the largest outbreak to date.
At this time, no confirmed cases of Ebola were reported in the week to January 3, 2016. Guinea, Liberia, and Sierra Leone have all now succeeded in stopping human-to-human transmission linked to the original outbreak in West Africa. Outbreaks occur intermittently in tropical regions of sub-Saharan Africa.