POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 天花是一种威胁生命的疾病，由接触天花病毒引起，天花病毒是一种高度传染性的病原体，被认为是一种生物威胁剂。 如果发生意外或故意的天花气雾剂暴露，目前没有推荐的天花暴露后预防和/或治疗药物。 西多福韦是一种抗病毒药物，可用于治疗生物攻击事件中的感染。 正在开发一种吸入西多福韦干粉制剂，用于接触后预防和治疗天花气溶胶暴露。 在多项小鼠研究中，吸入西多福韦已显示出对各种痘模型高度有效，与注射给药相比，在肺组织中产生长期活性和保留。 静脉注射西多福韦虽然有效，但会导致肺部水平降低，严重的肾毒性，需要卫生保健工作者进行治疗。 可吸入的西多福韦，或者，导致在肺中的高药物水平，绕过肾脏，并自我管理。 首先，我们将评估吸入版本的西多福韦在兔痘病毒感染模型。 兔痘是研究痘病毒的理想动物模型;当动物通过气溶胶实验感染病毒时，它会引起与兔天花相似的综合征。 该抗病毒评价模型将评估西多福韦是否有效抑制暴露于气溶胶的兔子的感染，同时不引起过度的肾损伤或其他不必要的不良反应。 基于兔痘研究的初步结果，我们将使用先进的非人灵长类动物天花模型（猴中的雾化猴痘）进行有效性研究，以证明在非人灵长类动物中通过吸入给予抗病毒药物反映了在人类中的情况，并且当在该致死模型中用作暴露后治疗时，此类浓度与灵长类动物存活率呈正相关。 这些研究的结果将建立相对安全性和临床前疗效的西多福韦作为一个可行的抗病毒治疗天花。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Smallpox is a life threatening disease caused by exposure to variola virus, a highly contagious pathogen that is considered a biological threat agent. In the event of an accidental or deliberate aerosol exposure of variola, there are currently no recommended drugs for postexposure prophylaxis and/or treatment for smallpox. Cidofovir is an antiviral drug that can be used to treat infection in the event of a biological attack. An inhaled cidofovir dry-powder formulation is being developed to be used in post-exposure prophylaxis and treatment of aerosol exposure to variola. Inhaled cidofovir has been shown in multiple mouse studies to be highly efficacious against various pox models, producing long-term activity and retention in the lung tissue compared to injectable administration. Intravenous administration of cidofovir, although efficacious, results in lower lung levels, severe kidney toxicity, and requires a health-care worker to implement treatment. Inhalable cidofovir, alternatively, results in high drug levels in the lung, bypasses the kidneys, and is self-administered. Initially, we will evaluate the inhalable version of cidofovir in a rabbit model of poxvirus infection. Rabbitpox is an ideal animal model for studying poxviruses; it causes a syndrome similar to smallpox in rabbits when the animals are experimentally infected with the virus by aerosol. This antiviral evaluation model will assess if cidofovir effectively inhibits infection in aerosol-exposed rabbits while not causing undue kidney damage or other unwanted adverse effects. Based upon the preliminary results from the rabbitpox studies, we will use an advanced nonhuman primate model of smallpox disease (aerosolized monkeypox in monkeys) to perform efficacy studies to demonstrate that delivery of the antiviral drug by inhalation in the nonhuman primate mirrors that in humans and that such concentrations are positively associated with primate survival when used as a postexposure therapeutic in this lethal model. Results of these studies will establish the relative safety and preclinical efficacy of reformulated cidofovir as a viable antiviral therapeutic against smallpox.