Abstract
CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.
Highlights
Variola virus—the causative agent of human smallpox—has been eliminated from the natural environment, a human threat from weaponized variola virus remains [1,2,3]
We have used the intradermal inoculation rabbitpox virus (RPV) model to evaluate the efficacy of CMX001 as a potential prophylactic treatment for orthopoxvirus infection [19]
We reviewed the salient features of the rabbitpox virus infection of rabbits as a model system for systemic orthopoxvirus disease, key features of human smallpox, monkeypox and certain adverse complications arising from vaccination
Summary
Variola virus—the causative agent of human smallpox—has been eliminated from the natural environment, a human threat from weaponized variola virus remains [1,2,3]. While the disease progression of intradermal and aerosol infections are clinically similar, it is important to note several differences between the two routes of infection, each offering specific key animal model advantages for human smallpox. The disease symptoms requiring euthanasia in both routes is respiratory distress, this occurs 1–2 days sooner in aerosol infected animals than in intradermally infected rabbits, most likely due to differences in the primary site of infection We have used the intradermal inoculation RPV model to evaluate the efficacy of CMX001 as a potential prophylactic treatment for orthopoxvirus infection [19] In this communication, our results demonstrate that CMX001 is effective in preventing mortality and reducing morbidity when administered prior to virus exposure and early in infection as compared to untreated animals
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