Advanced antisense therapies for postexposure protection against lethal filovirus infections

Warren, Travis K.; Warfield, Kelly L.; Wells, Jay; Swenson, Dana L.; Donner, Kelly S; Tongeren, Sean A. Van; Garza, Nicole L.; Liu, Dong; Mourich, Dan V.; Crumley, Stacy; Nichols, Donald K.; Iversen, Patrick L.; Bavari, Sina

doi:10.1038/nm.2202

Cited by 183 publications

(171 citation statements)

References 18 publications

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“…In the recent past, experimental postexposure treatments for filovirus infections have included hyperimmune equine IgG (9), EBOV-specific human monoclonal IgG antibody (16), wholeblood transfusions from convalescent survivors (8), recombinant IFN (13), recombinant nematode anticoagulant protein C2 (19), recombinant human activated protein C (20,21), recombinant vesicular stomatitis virus vectors (22)(23)(24)(25), siRNAs (26), and phosphorodiamidate morpholino oligomers (27). A summary of these efforts is detailed in Table 2.…”

Section: Discussionmentioning

confidence: 99%

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Dye

Herbert²,

Kuehne³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

242

215

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Antibody therapies to prevent or limit filovirus infections have received modest interest in recent years, in part because of early negative experimental evidence. We have overcome the limitations of this approach, leveraging the use of antibody from nonhuman primates (NHPs) that survived challenge to filoviruses under controlled conditions. By using concentrated, polyclonal IgG antibody from these survivors, we treated filovirus-infected NHPs with multiple doses administered over the clinical phase of disease. In the first study, Marburg virus (MARV)-infected NHPs were treated 15 to 30 min postexposure with virus-specific IgG, with additional treatments on days 4 and 8 postexposure. The postexposure IgG treatment was completely protective, with no signs of disease or detectable viremia. MARV-specific IgM antibody responses were generated, and all macaques survived rechallenge with MARV, suggesting that they generated an immune response to virus replication. In the next set of studies, NHPs were infected with MARV or Ebola virus (EBOV), and treatments were delayed 48 h, with additional treatments on days 4 and 8 postexposure. The delayed treatments protected both MARV- and EBOV-challenged NHPs. In both studies, two of the three IgG-treated NHPs had no clinical signs of illness, with the third NHP developing mild and delayed signs of disease followed by full recovery. These studies clearly demonstrate 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.

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Section: Discussionmentioning

confidence: 99%

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Dye

Herbert²,

Kuehne³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

242

215

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“…Antisense technology forms the basis of other promising treatments [70]. Antisense refers to short DNA or RNA sequences, termed oligonucleotides, which are designed to be complementary to a specific gene sequence.…”

Section: Treatmentmentioning

confidence: 99%

“…It has been suggested to be an effective post-exposure treatment regimen for EBOV-infected people [75]. Used as candidate antiviral drugs, both the siRNAs and advanced antisense therapeutics (phosphorodiamidate morpholino oligomers, PMO) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L-protein have been found to prevent EVD in non-human primates [70,75]. Very recently, Investigational New Drug (IND) applications have been approved by the US FDA, and phase I clinical trials have been initiated for two small-molecule therapeutics: anti-sense PMOs (AVI-6002, AVI-6003) and lipid nanoparticle (LNP)/siRNA (TKM-Ebola).…”

Section: Treatmentmentioning

confidence: 99%

Ebola from emergence to epidemic: the virus and the disease, global preparedness and perspectives

Dhama

Malik

et al. 2015

J Infect Dev Ctries

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Humans constantly encounter threats from many infectious, zoonotic, and devastating pathogens. Outbreaks of severe acute respiratory syndrome (SARS), bird flu, and swine flu posing pandemic threats have compelled health agencies to follow global preparedness for combating the emerging deadly pathogens. The outbreak in West Africa of highly contagious Ebola viral disease (EVD) that started in Guinea in December 2013, assumed global proportions to become the largest outbreak of EVD and the most prominent international health concern. With fatality rates of nearly 50%-90%, it has claimed, as of 11 April 2015, 10,619 human lives out of a total of 25,626 cases reported worldwide. Ebola virus (EBOV), a member of Filoviridae family, is associated with severe, often lethal, hemorrhagic fever disease in humans and animals. The animal hosts, including non-human primates and reservoir hosts (fruit bats), play a significant role in transmission and maintenance of EBOV in nature. Although no approved vaccine for the prevention of EVD currently exists, disease control can be greatly enhanced by timely laboratory confirmation through blood tests using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Adherence to strict sanitary and hygienic measures, monitoring and surveillance of EBOV, as well as quarantine checks on international trade, transport, and visitors from affected countries are mandatory to prevent and control the spread of EVD. This review describes the salient properties of EBOV and the development of novel diagnostics, vaccines, and control strategies for this emerging disease of high public health concern and international emergency.

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“…Surprisingly, a mutation in the highly conserved interferon inhibitory domain of VP35 (C4116T) introduces a phenylalanine, characteristic of Sudan EBOV, but never previously observed in EBOV-Zaire. Another mutation in VP35, G3151A (ArgRLys), lies in the sequence targeted by AVI-7539, a phosphorodiamidate morpholino oligomer (PMO)-based therapeutic candidate 6 . Studies of the phenotypic consequences of such mutations on viral components directly interacting with the host immune response could provide key insights into their epidemic potential, and also inform the therapeutic options currently considered for deployment 7,8 .…”

mentioning

confidence: 99%

Distinct lineages of Ebola virus in Guinea during the 2014 West African epidemic

Simon‐Lorière

Faye

Koivogui

et al. 2015

Nature

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An analysis of 85 Ebola virus sequences collected in Guinea from July to November 2014 provides insight into the evolution of the Ebola virus responsible for the epidemic in West Africa; the results show sustained transmission of three co-circulating lineages, each defined by multiple mutations. Supplementary information The online version of this article (doi:10.1038/nature14612) contains supplementary material, which is available to authorized users.

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Advanced antisense therapies for postexposure protection against lethal filovirus infections

Cited by 183 publications

References 18 publications

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Ebola from emergence to epidemic: the virus and the disease, global preparedness and perspectives

Distinct lineages of Ebola virus in Guinea during the 2014 West African epidemic

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