Advanced antisense therapies for postexposure protection against lethal filovirus infections

  title={Advanced antisense therapies for postexposure protection against lethal filovirus infections},
  author={Travis K Warren and Kelly L. Warfield and Jay B. Wells and Dana L. Swenson and Kelly S Donner and Sean A. Van Tongeren and Nicole L Garza and Lian Cheng Dong and Dan V. Mourich and Stacy Crumley and Donald K. Nichols and Patrick L. Iversen and Sina Bavari},
  journal={Nature Medicine},
Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30–60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus… 
Potential Vaccines and Post-Exposure Treatments for Filovirus Infections
Current progress in the development of filovirus therapeutics and vaccines is outlined herein with respect to their current level of testing, evaluation, and proximity toward human implementation, specifically with regard to human clinical trials, nonhuman primate studies, small animal studies, and in vitro development.
Post-exposure treatments for Ebola and Marburg virus infections
The current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules are summarized, to outline how the current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively.
Ebola vaccine, therapeutics, and diagnostics.
Previous researches and recent advances on the development of vaccine, therapeutics, and diagnostics for Ebola virus disease (EVD) are reviewed.
Post-exposure therapy of filovirus infections.
Anti-infectives: Post-exposure antisense protection against lethal filoviruses?
An antisense approach that shows post-exposure efficacy in non-human primate models is presented, suggesting that the window for effective treatment in primates may be wider than as yet tested, and would make PMOplus-based drugs effective against naturally occurring outbreaks or even against the deliberate release of Ebola, Marburg and potentially other pathogenic viruses.
Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
It is shown that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells, and exhibits broad-spectrum antiviral activity against numerous viruses.
Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease
It is demonstrated that postexposure antibody treatments can protect NHPs and open avenues for filovirus therapies for human use using established Food and Drug Administration-approved polyclonal or monoclonal antibody technologies.
Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment
Recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever are summarized and the utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms are discussed.
Therapeutics Against Filovirus Infection.
The ability to manage outbreaks with medical interventions beyond supportive care will require clinical trial design that will balance the benefits of the patient and scientific community.
Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™
It is shown that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge, and ZMapp exceeds the efficacy of any other therapeutics described so far.


Gene-Specific Countermeasures against Ebola Virus Based on Antisense Phosphorodiamidate Morpholino Oligomers
A combination of EBOV-specific PMOs targeting sequences of viral mRNAs for the viral proteins (VPs) VP24, VP35, and RNA polymerase L protected rodents in both pre- and post-exposure therapeutic regimens.
Recombinant Vesicular Stomatitis Virus Vector Mediates Postexposure Protection against Sudan Ebola Hemorrhagic Fever in Nonhuman Primates
This is the first demonstration of complete postexposure protection against an Ebola virus in nonhuman primates and provides further evidence that postex exposure vaccination may have utility in treating exposures to filoviruses.
Effective Post-Exposure Treatment of Ebola Infection
It is shown that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge.
Disease modeling for Ebola and Marburg viruses
An overview of the clinical picture and the pathology/pathogenesis of human filovirus infections is provided and the current animal model options are discussed and compared with regard to their value in different applications.
Postexposure Treatment of Marburg Virus Infection
Rhesus monkeys are protected from disease when a recombinant vesicular stomatitis virus–based vaccine is administered 20–30 min after infection with Marburg virus. We protected 5/6 monkeys when this
Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection
The abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection are reported on.
Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates.
An RNA replicon, based upon Venezuelan equine encephalitis (VEE) virus, was used as a vaccine vector; the VEE structural genes were replaced by genes for MBGV GP, nucleoprotein (NP), VP40, VP35, VP30, or VP24.
How Ebola and Marburg viruses battle the immune system
The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents.