Detrimental drift
Genetic drift in Ebola virus could render monoclonal antibodies, siRNA treatments ineffective
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PHILADELPHIA—The tendency of viruses to mutate makes attempts to vaccinate individuals an ongoing battle, a struggle that could now provide a new roadblock for researchers trying to develop therapies against Ebola. Following investigation of genetic changes in the Ebola virus, scientists from the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID), Harvard University and the Massachusetts Institute of Technology (MIT) have published results in mBio concluding that the virus' genomic drift, or the natural evolution that characterizes viruses, over time could alter it enough to block the action of therapies that would have otherwise been effective at targeting the virus' genetic sequences.
The types of drugs that are based on genetic sequences and most likely to lose their effectiveness include monoclonal antibodies, small-interfering RNA and phosphorodiamidate morpholino oligomer (PMO) drugs. All the drugs being evaluated against the current outbreak were developed off of Ebola virus strains from outbreaks in 1976 and 1995. While none of these therapies have received U.S. Food and Drug Administration approval, some of them are being used under a World Health Organization emergency protocol.
The current strain, known as EBOV/Mak, was compared with those two previous strains, and in each comparison, more than 600 genetic mutations were found. The team then focused on mutations that occurred only in the genetic sequences targeted by the potential therapies, and of those, 10 new mutations were discovered that could interfere with the drugs' effectiveness. Three of those mutations presented during the current outbreak.
“Based on our findings, the virus has changed and is continuing to change,” said CPT Jeffrey Kugelman, Ph.D., the paper’s first author. Kugelman, a viral geneticist at USAMRIID, is currently working at the Liberian Institute for Biomedical Research, helping local officials to set up an onsite genomic sequencing capability for Ebola patient samples.
Hemispherx Biopharma, Inc. is among the companies advancing potential therapeutics for treating Ebola, including its two platform drugs Alferon N and Ampligen, both of which have demonstrated anti-EBOV activity. These drugs both have multifaceted mechanisms of action that work through cellular “molecular cascades” as opposed to targeting viral protein or genetic sequences, and since cellular antiviral pathways of innate immunity are not subject to the mutations typical of viruses, it is thought this approach could demonstrate biological activity even when the virus mutates.
Alferon N is a natural source, multi-species alpha interferon approved in the U.S. for the treatment of refractory or recurring external genital warts caused by human papilloma virus in patients 18 years of age, or older. The USAMRIID has reported that Alferon has shown positive results in vitro against Ebola, though clinical trial data is needed to determine the drug's human efficacy.
Hemispherx' Ampligen is another experimental therapeutic that falls into a class of specifically configured RNA compounds targeted against diseases with viral causation, among others. As the Ebola virus specifically inhibits the dsRNA in cells—RNA that could otherwise trigger a strong antiviral response—Ampligen could serve to overcome the diminished immune response. The USAMRIID, as well as other academic and research institutions, have reported that the compound has shown positive results against the Ebola virus in vitro, and animal testing is underway.
