Using biomarkers to stage disease progression in a lethal mousepox model treated with CMX001.
BACKGROUND
The emergence of human monkeypox and the potential use of recombinant variola and monkeypox viruses as biological terrorist agents have necessitated the development of therapeutic and prophylactic therapies. The primary, or index, cases of smallpox and/or human monkeypox will likely be identified by a characteristic rash. Effective biomarkers will be required to monitor disease progression, guide the choice of therapeutic intervention strategies and evaluate their efficacies. To address this we have evaluated several biomarkers of disease in a lethal mousepox model.


METHODS
The efficacy of a single dose of a hexadecyloxypropyl ester of cidofovir (CMX001) at 20, 25 and 30 mg/kg doses administered on days 4, 5, 6 and 7 post-infection was evaluated in A/Ncr mice intranasally infected with low doses of ectromelia virus (<20 plaque-forming units). Mice were monitored for weight loss, blood interferon-gamma levels, alanine aminotransferase (ALT), aspartate aminotransferase, viral DNA copies and neutrophilia levels to stage disease progression.


RESULTS
We have used these biomarkers to establish the optimal dosing regimen for treatment and reveal that a single dose of 25 mg/kg of CMX001 can be efficacious at treating lethal mousepox when administered on days 4 or 5 post-infection. This dose significantly reduces ALT, interferon-gamma and DNA copies found in the blood of infected animals.


CONCLUSIONS
A single dose regimen of CMX001 is efficacious at treating mousepox. Disease progression and antiviral efficacy can be monitored using several biomarkers that could readily be used in the case of a human monkeypox or smallpox outbreak.
Parker
Scott
S
Department of Molecular Microbiology and Immunology, St Louis University Medical School, St Louis, MO, USA.
Schriewer
Jill
J
Oberle
Christina
C
Robertson
Alice
A
Lanier
Randall
R
Painter
George
G
Buller
R Mark
RM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004481:Ectromelia virus / Q000472:pathogenicity*; D004482:Ectromelia, Infectious / Q000188:drug therapy* / Q000503:physiopathology* / Q000821:virology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D051379:Mice; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D015431:Weight Loss
D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D063065:Organophosphonates; C525733:brincidofovir; D007371:Interferon-gamma; D003596:Cytosine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase