Invited Speaker

Advancement of Antisense Therapy for Filovirus Infections
Travis K. Warren, Kelly L. Warfield, Jay Wells, Dana L. Swenson, Candace Lovejoy, Patrick L. Iversen, and Sina Bavari
USA

Marburg virus (MARV) and Ebola virus (EBOV), members of the Filoviridae family of viruses, are highly pathogenic viruses responsible for viral hemorrhagic fever, an acute and rapidly progressing disease, with case fatality rate of up to 90%. There exists an urgent need to develop effective vaccines and therapies for use during outbreaks and following potential bioterrorism events. Previously, we have shown that a prophylactic regimen of synthetic antisense phosphorodiamidate oligomers (PMOs) complementary to viral transcripts partially protect EBOV-infected rhesus macaques against lethal challenge. Here we describe improved efficacy of a new class of positively charged PMO molecules, designated PMO+, for treatment of both EBOV and MARV infections. A therapeutic regimen of PMO+ agents targeting EBOV VP35 and VP24 transcripts conferred a high degree of protection in rodent models of EBOV infection and protected 60% or greater of infected rhesus macaques when delivered either by a combination of subcutaneous and intraperitoneal injections or by intravenous injections. Post-challenge delivery of PMO+ agents specific to MARV NP and VP24 transcripts completely protected cynomolgus macaques against lethal MARV challenge. Administration of PMO+ agents reduced viremia, dampened pro-inflammatory cytokine responses, and reduced serum indicators of liver pathology in filovirus-infected primates. The PMO+ agents used in these evaluations have produced the highest degree of survival yet for a therapeutic agent in nonhuman primate models of both EBOV and MARV infection, and represent a promising class of antisense therapeutic agents for treatment of highly pathogenic viral infections in humans.