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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

Antibody responses results.MARV-specific anti-GP (A) IgM and (B) IgG antibody titers for each animal at day 10 and day 14 post challenge.
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pntd.0004456.g005: Antibody responses results.MARV-specific anti-GP (A) IgM and (B) IgG antibody titers for each animal at day 10 and day 14 post challenge.

Mentions: MARV-specific IgM was not detected in any of the AVI-7288-treated animals before day 8 PI, at which point it was found in low titers (1:10) in 3 of 29 animals. By day 14 PI, MARV-specific IgM was detected in all surviving animals and generally reached a maximum with titers ranging from 1:30 to 1:810 (Fig 5A). A gradual reduction in IgM was observed in all animals through day 41 PI. MARV-specific IgG was first detected on day 10 PI in 6 of 24 animals (Fig 5B). By day 14 PI, MARV-specific IgG was detected in all surviving animals and titers generally increased from day 14 to day 21 PI and plateaued thereafter through the end of the study with titers ranging from 1:90 to 1:2430. Elevated levels of several proinflammatory chemokines, including Eotaxin, IP-10, and MCP-1, were observed late in infection (peaking at days 8–14 PI) in animals in all treatment groups. However, peak levels of Eotaxin, MCP-1 (Fig 6A), and IP-10 were lower in AVI-7288-treated animals. Saline-treated animals also showed an increased in MDC, TARC, IL-6, and MIP1β prior to death, which on average were higher than observed in the AVI-7288 treated animals (S11 Fig).


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)

Antibody responses results.MARV-specific anti-GP (A) IgM and (B) IgG antibody titers for each animal at day 10 and day 14 post challenge.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0004456.g005: Antibody responses results.MARV-specific anti-GP (A) IgM and (B) IgG antibody titers for each animal at day 10 and day 14 post challenge.
Mentions: MARV-specific IgM was not detected in any of the AVI-7288-treated animals before day 8 PI, at which point it was found in low titers (1:10) in 3 of 29 animals. By day 14 PI, MARV-specific IgM was detected in all surviving animals and generally reached a maximum with titers ranging from 1:30 to 1:810 (Fig 5A). A gradual reduction in IgM was observed in all animals through day 41 PI. MARV-specific IgG was first detected on day 10 PI in 6 of 24 animals (Fig 5B). By day 14 PI, MARV-specific IgG was detected in all surviving animals and titers generally increased from day 14 to day 21 PI and plateaued thereafter through the end of the study with titers ranging from 1:90 to 1:2430. Elevated levels of several proinflammatory chemokines, including Eotaxin, IP-10, and MCP-1, were observed late in infection (peaking at days 8–14 PI) in animals in all treatment groups. However, peak levels of Eotaxin, MCP-1 (Fig 6A), and IP-10 were lower in AVI-7288-treated animals. Saline-treated animals also showed an increased in MDC, TARC, IL-6, and MIP1β prior to death, which on average were higher than observed in the AVI-7288 treated animals (S11 Fig).

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