The authors had previously shown that the nucleic acid analogues phosphorodiamidate morpholino oligomers (PMOs), engineered to knock down the expression of three Zaire Ebola virus (ZEBOV) proteins, showed pre-exposure efficacy in a rhesus macaque model. Moreover, an improved, positively charged class of PMOs that contains piperazine linkages (PMOplus) protected mice against a lethal ZEBOV challenge. In their current report, the authors used mouse and guinea pig models to further enhance the PMOplus approach by combining eVP24-specific and eVP35-specific PMOplus molecules and by optimizing piperazine linkages, resulting in the combination drug AVI-6002. In a proof-of-concept study, rhesus macaques were infected with lethal doses of ZEBOV and treated with AVI-6002 by both subcutaneous and intraperitoneal injection 30–60 minutes after infection. An untreated control animal died on day 7, but five out of eight AVI-6002-treated macaques survived infection. A second set of experiments in 20 animals treated with AVI-6002 intravenously showed a dose response, with three out of five animals surviving at the two highest doses, one out of five animals at the medium dose and no survivors at the lowest dose. Blood analysis showed that viral load correlated with survival and that markers of liver damage (aspartate aminotransferase) and pro-inflammatory cytokines and chemokines (interleukin-6 and monocyte chemotactic protein 1) were suppressed in survivors. This indicates that the drug inhibits viral replication and limits liver damage and potentially harmful inflammation.
A similar strategy was also effective against Marburg virus, for which a combination of Marburg virus VP24-directed and nucleoprotein-directed PMOplus molecules were formulated into the drug AVI-6003. In pilot experiments, all 13 cynomolgus monkeys that were infected with Marburg virus and then treated with two different doses of AVI-6003, either by subcutaneous and intraperitoneal administration or by intravenous injection, survived regardless of treatment strategy. A second randomized, multiple dose study in 20 monkeys showed 100% survival in the highest dose group and 60% survival in the lower treatment dose groups.
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