Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys

Geisbert, Thomas W.; Hensley, Lisa E.; Jahrling, Peter B.; Larsen, Tom; Geisbert, Joan B.; Paragas, Jason; Young, Howard A.; Fredeking, Terry; Rote, William E.; Vlasuk, George P.

doi:10.1016/s0140-6736(03)15012-x

Cited by 349 publications

(289 citation statements)

References 19 publications

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“…There have been several studies investigating the use of compounds that modulate blood coagulation disorders as a non-antiviral approach to treating filovirus disease. Recombinant nematode anticoagulant protein c2 (rNAPc2) blocks the activity of a complex comprising coagulation factor VIIa and tissue factor and was administered shortly after challenge (beginning immediately or on day 1) to groups of rhesus monkeys exposed to EBOV (Kikwit strain) 55 ; 33% of the animals survived (TABLE 4). In rhesus monkeys challenged with MARV (Angola strain), rNAPc2 treatment resulted in the survival of only one of six treated animals 50 .…”

Section: Modulation Of the Coagulation Systemmentioning

confidence: 99%

“…Systematic studies in experimentally infected NHPs suggest that monocytes, macrophages and dendritic cells are the early replication sites for EBOV and MARV 41,48,51 . Filovirus infection of mononuclear phagocytes is thought to trigger a series of events that includes the production and release of the procoagulant protein tissue factor 54,55 and an assortment of pro-inflammatory cytokines, chemokines and free radical species in NHPs and humans 48,51,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] . This dysregulated host response likely plays a greater role in the development of the observed pathology than any structural damage caused by viral replication in host cells and/or tissues.…”

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confidence: 99%

“…Results from many studies have shown biochemical and histological evidence of disseminated intravascular coagulation in both experimentally infected NHPs and humans 19,20,22,23,40,[44][45][46][49][50][51]53,54,70,[73][74][75][76][77][78][79] . The mechanisms that cause these coagulation disorders are not fully understood, but the expression or release of tissue factor from filovirus-infected monocytes and macro phages seems to play a role 54,55 . However, the coagulation irregularities noted during filovirus haemorrhagic fever could be caused by other factors, particularly at the end stage of disease.…”

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Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Modulation Of the Coagulation Systemmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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“…1). In addition to cytokine effects on vascular permeability, causes of excessive bleeding can include plummets in platelet numbers, severe liver damage and the activation of tissue factor in monocytes and macrophages 92 . The time from infection to death is generally 1-2 weeks, with some variability depending on the virus and host species, as well as on initial dose 93 .…”

Section: Box 1 | Filovirus-disease Basicsmentioning

confidence: 99%

How Ebola and Marburg viruses battle the immune system

2007

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PantropicTending towards the capacity to infect a wide range of cells and organs. CoagulopathyRefers to a group of conditions of the blood-clotting system in which bleeding is prolonged and excessive. Cell tropismA virus's affinity for or tendency towards preferential infection of certain cells. How Ebola and Marburg viruses battle the immune systemMansour Mohamadzadeh* ‡ , Lieping Chen ‡ , and Alan L. Schmaljohn* Abstract | 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. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself. R E V I E W S Report Documentation PageForm Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

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“…Based on these data, it was postulated that blocking factor VIIa (FVIIa)/TF might be beneficial after EBOV infection (Ref. 65). In a preliminary study, nine ZEBOV-infected monkeys were treated with a protein that prevents blood clotting -recombinant nematode anticoagulant protein c2 (rNAPc2) -while three ZEBOV-infected monkeys were given a placebo control.…”

Section: Regulation Of the Coagulation Systemmentioning

confidence: 99%

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Geisbert

Hensley

2004

Expert Rev. Mol. Med.

112

106

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Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicised isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.

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Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys

Abstract: Post-exposure protection with rNAPc2 against Ebola virus in primates provides a new foundation for therapeutic regimens that target the disease process rather than viral replication.

Cited by 349 publications

References 19 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

How Ebola and Marburg viruses battle the immune system

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

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