A lack of knowledge about the pathogenesis of the filoviruses Ebola virus (EBOV) and Marburg virus, as well as the special containment conditions required to study them, has proved to be a significant obstacle to the development of therapies for these infections. Writing in PLoS Pathogens, Warfield and colleagues describe the first use of a new generation of antisense technology that inhibits mRNA translation of specific viral proteins (VPs), an approach that was effective against lethal EBOV infection and has implications for the treatment of other infections caused by viral pathogens.
Warfield and colleagues designed antisense phosphorodiamidate morpholino oligomers (PMOs) — oligonucleotide analogues incorporating a phosphorodiamidate link and a morpholine ring — to target EBOV VP24, VP35 and RNA-dependent RNA polymerase (L protein). In contrast to oligonucleotides, PMOs have several drug-like properties — for example, they are non-ionic in character and therefore permeate cells more easily, are resistant to degradation in cells and do not seem to induce an interferon response, all of which make them attractive as potential therapeutic agents.
Promising results with the three EBOV-specific PMOs from a cell-based assay and survival tests in mice and guinea pigs prompted the authors to carry out a small proof-of-concept study in Rhesus macaques. The monkeys were treated with either the VP35-specific PMO or a combination of the VP24, VP35 and L protein PMOs 2 days before exposure to lethal EBOV infection. Whereas monkeys receiving only the VP35-specific PMO succumbed to lethal EBOV infection, 75% of those monkeys receiving the combination treatment survived. Surviving monkeys developed low to moderate viraemia, and testing of their immune response 28 days after infection showed high levels of anti-EBOV antibodies and T-cell responses, indicating a prominent role for the immune system in protection from lethal infection.
Using a combination of antisense PMOs to target multiple viral genes seems to slow EBOV replication to a level that gives the host's innate immune system time to mount a protective antiviral immune response. PMOs have appropriate safety profiles for use in humans, and can be easily produced in large quantities. Moreover, the hit-to-lead optimization of sequence-based approaches, such as those using antisense PMOs, can usually be done rapidly, and so can accelerate the drug discovery process for such compounds.
Previous strategies to treat EBOV infection focused on inhibiting viral mRNA replication or strengthening the host's immune response, but these approaches had limited success. The results reported by Warfield and colleagues could contribute to the development of a new strategy to combat a wide range of viral infections. The next step will be to enhance the therapeutic potential by targeting the PMOs to the specific locations where viral replication occurs.
ORIGINAL RESEARCH PAPER
Warfield, K. L. et al. Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers. PLoS Pathogens 13 Jan 2006 (10.1371/journal.ppat.0020001)
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Barton, S. Antisense PMOs protect against Ebola virus. Nat Rev Drug Discov 5, 106 (2006). https://doi.org/10.1038/nrd1969