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Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques.

Warren TK, Whitehouse CA, Wells J, Welch L, Charleston JS, Heald A, Nichols DK, Mattix ME, Palacios G, Kugleman JR, Iversen PL, Bavari S - PLoS Negl Trop Dis (2016)

Bottom Line: Survival was the primary endpoint of the study.While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI).These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.

ABSTRACT
Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

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Related in: MedlinePlus

Photomicrographs of liver from two macaques that were challenged with MARV.(A) Liver from a control animal that died on day 11 PI has an area of hepatocellular degeneration and necrosis (upper right corner). (B) IHC of a replicate section of area shown in A demonstrating abundant brown-staining MARV antigen in the lesion. (C) Normal liver from an animal that was treated with AVI-7288 beginning 96 h PI and which survived the viral challenge. (D) IHC of a replicate section of area shown in C demonstrating that no MARV antigen is present. 40X objective magnification for all photos. Hematoxylin & eosin stain for A and C. Immunoperoxidase with hematoxylin counter-stain for B and D.
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pntd.0004456.g007: Photomicrographs of liver from two macaques that were challenged with MARV.(A) Liver from a control animal that died on day 11 PI has an area of hepatocellular degeneration and necrosis (upper right corner). (B) IHC of a replicate section of area shown in A demonstrating abundant brown-staining MARV antigen in the lesion. (C) Normal liver from an animal that was treated with AVI-7288 beginning 96 h PI and which survived the viral challenge. (D) IHC of a replicate section of area shown in C demonstrating that no MARV antigen is present. 40X objective magnification for all photos. Hematoxylin & eosin stain for A and C. Immunoperoxidase with hematoxylin counter-stain for B and D.

Mentions: Results from post-mortem anatomic pathology analyses indicated that all of the PBS-treated control animals developed fatal MARV infections with gross and histologic lesions and immunohistochemistry findings typical of those previously seen in cynomolgus macaques that had been experimentally infected with MARV. The organs that were consistently and most severely affected were the liver and spleen. Liver lesions consisted of multiple foci of hepatocellular degeneration and necrosis accompanied by varying degrees of acute inflammation (Fig 7A); IHC demonstrated that abundant MARV antigen was present within these lesions (Fig 7B). In the spleens, there was moderate to marked lymphoid depletion of the white pulp, usually accompanied by lysis of lymphocytes and deposition of fibrin in the adjacent red pulp (Fig 8A). Large amounts of viral antigen were present within histiocytic cells in the red and white pulp as well as in the extracellular fibrin (Fig 8B).


Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques.

Warren TK, Whitehouse CA, Wells J, Welch L, Charleston JS, Heald A, Nichols DK, Mattix ME, Palacios G, Kugleman JR, Iversen PL, Bavari S - PLoS Negl Trop Dis (2016)

Photomicrographs of liver from two macaques that were challenged with MARV.(A) Liver from a control animal that died on day 11 PI has an area of hepatocellular degeneration and necrosis (upper right corner). (B) IHC of a replicate section of area shown in A demonstrating abundant brown-staining MARV antigen in the lesion. (C) Normal liver from an animal that was treated with AVI-7288 beginning 96 h PI and which survived the viral challenge. (D) IHC of a replicate section of area shown in C demonstrating that no MARV antigen is present. 40X objective magnification for all photos. Hematoxylin & eosin stain for A and C. Immunoperoxidase with hematoxylin counter-stain for B and D.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764691&req=5

pntd.0004456.g007: Photomicrographs of liver from two macaques that were challenged with MARV.(A) Liver from a control animal that died on day 11 PI has an area of hepatocellular degeneration and necrosis (upper right corner). (B) IHC of a replicate section of area shown in A demonstrating abundant brown-staining MARV antigen in the lesion. (C) Normal liver from an animal that was treated with AVI-7288 beginning 96 h PI and which survived the viral challenge. (D) IHC of a replicate section of area shown in C demonstrating that no MARV antigen is present. 40X objective magnification for all photos. Hematoxylin & eosin stain for A and C. Immunoperoxidase with hematoxylin counter-stain for B and D.
Mentions: Results from post-mortem anatomic pathology analyses indicated that all of the PBS-treated control animals developed fatal MARV infections with gross and histologic lesions and immunohistochemistry findings typical of those previously seen in cynomolgus macaques that had been experimentally infected with MARV. The organs that were consistently and most severely affected were the liver and spleen. Liver lesions consisted of multiple foci of hepatocellular degeneration and necrosis accompanied by varying degrees of acute inflammation (Fig 7A); IHC demonstrated that abundant MARV antigen was present within these lesions (Fig 7B). In the spleens, there was moderate to marked lymphoid depletion of the white pulp, usually accompanied by lysis of lymphocytes and deposition of fibrin in the adjacent red pulp (Fig 8A). Large amounts of viral antigen were present within histiocytic cells in the red and white pulp as well as in the extracellular fibrin (Fig 8B).

Bottom Line: Survival was the primary endpoint of the study.While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI).These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.

ABSTRACT
Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

Show MeSH
Related in: MedlinePlus