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Genetic Changes in Ebola Virus Could Hinder Potential Treatments

Drugs have to keep up with ‘genomic drift’

Researchers have tracked the genetic mutations that have occurred in the Ebola virus during the last four decades. Their findings, published in mBio, the online journal of the American Society for Microbiology, identified changes in the current West African outbreak strain that could potentially interfere with experimental, sequence-based therapeutics.

“We wanted to highlight an area where genomic drift, the natural process of evolution on this RNA virus genome, could affect the development of therapeutic countermeasures,” said senior author Dr. Gustavo Palacios.

Many of the most promising drugs being developed to fight Ebola are therapeutics that bind to and target a piece of the virus’s genetic sequence or a protein sequence derived from that genetic sequence. If that sequence changes because of genetic drift (the natural evolution of the virus over time), then the drugs may not work effectively.

“Our work highlights the genetic changes that could affect these sequence-based drugs that were originally designed in the early 2000s based on virus strains from outbreaks in 1976 and 1995,” Palacios said.

The team compared the entire genomic sequence of the current outbreak strain, EBOV/Mak, with that of two other Ebola virus variants –– one from an outbreak in Yambuku, Zaire (now the Democratic Republic of the Congo), in 1976 called EBOV/Yam-May, and one from an outbreak in Kikwit, Zaire, in 1995 called EBOV/Kik-9510621. The researchers found single-nucleotide polymorphisms (changes) in more than 600 spots, or about 3% of the genome.

Sequence-based drugs currently offer the best hope for future treatment of Ebola outbreaks but have not yet been approved by the FDA or any other regulatory agency, the researchers say. Because the World Health Organization adopted emergency containment measures for the ongoing West African outbreak, sequence-based drugs are currently being used to treat a handful of patients in experimental testing. A clinical trial for one of the therapies will begin in Sierra Leone in the coming months.

The team, which included researchers from Harvard University and the Massachusetts Institute of Technology, narrowed their search to only those mutations that changed the genetic sequences targeted by the various drugs. They found 10 new mutations that might interfere with the actions of monoclonal antibody siRNA (small-interfering RNA) or PMO (phosphorodiamidate morpholino oligomer) drugs currently being tested.

The authors concluded that drug developers should check whether these mutations affect the efficacy of their investigational Ebola teatments.

“The virus has not only changed since these therapies were designed, but it’s continuing to change,” said lead author U.S. Army Captain Jeffrey Kugelman. “Ebola researchers need to assess drug efficacy in a timely manner to make sure that valuable resources are not spent developing therapies that no longer work.”

Kugelman is currently in Liberia working with the local government to set up onsite genomics sequencing of samples from Ebola patients to obtain a real-time picture of how the virus changes as it is transmitted from person to person. He will be analyzing whether the virus’ genetic sequences that are key for diagnostic tests and drug interventions change over time.

“The virus mutates rapidly, and it’s an ongoing concern,” Kugelman said.

 Source: EurekAlert; January 20, 2015.

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