POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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，用于暴露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。 最初，我们使用药物级粉末形式的西多福韦（NanoFOVIR; Nf）治疗暴露于雾化兔痘病毒（RPXV）的兔子，以进一步评估直接药物递送至肺部的有效性。 用RPXV的H10-50 LD 50气雾剂感染未感染家兔。 三个亚组在t= 0 h感染后（PI）每天接受0.5、1.0或1.75 mg/kg雾化Nf，持续3天。 另一个亚组接受IV-西多福韦（每天10 mg/kg，PI 3天）或未治疗（CRL）。 结果显示，Nf组显示出50%（0.5）、80%（1.0）和100%（1.75）的抗病毒剂量相关存活率。 IV-西多福韦组中的所有动物均存活;所有CRL动物在PI第5-6天死亡。 在CRL +3d PI中出现RPX疾病的急性临床体征，包括厌食、高热、溢尿、呼吸困难、心动过速和痘病毒皮疹，直至死亡。 Nf（0.5，1.0）和IV-西多福韦组的临床症状较CRL组轻。 与CRL或IV-Cr组相比，Nf（1.75）组显示出对RPX的最小临床反应和剂量相关的肺部病变钝化。Nf在相当于IV-Cr剂量的10%时保护兔免受RPX的影响。 在Nf组的RPX疾病的临床发展中观察到剂量相关效应。 Nf（1.75）组和IV-西多福韦组对RPX诱导的病理改变有明显的减轻作用。 结果表明，可吸入Nf可能是一种可行的抗病毒药物，用于紧急PEP，并应在其他痘病毒疾病模型中进行评估（例如，非人灵长类动物中的MPX）。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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 for 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 used a pharmaceutical-grade powder version of cidofovir (NanoFOVIR; Nf) to treat rabbits exposed to aerosolized rabbitpox virus (RPXV) to further evaluate the effectiveness of direct drug delivery to the lung. Na¿ve rabbits were infected by aerosol with H10-50 LD50 of RPXV. Three subsets received aerosolized Nf at either 0.5, 1.0 or 1.75 mg/kg daily for 3 days postinfection (PI) at t=0h. Another subset received either IV-cidofovir (10 mg/kg daily, 3 days PI), or were untreated (CRL). Results showed Nf groups showed an antiviral-dose associated survival of 50% (0.5), 80% (1.0) and 100% (1.75). All animals in the IV-cidofovir group survived; all CRL animals died day 5-6 PI. Acute clinical signs of RPX disease, including anorexia, hyperthermia, rhinorrhea, dyspnea, tachycardia and poxviral rash, developed in the CRL +3d PI until death. Nf (0.5, 1.0) and the IV-cidofovir groups experienced milder clinical signs vs CRLs. The Nf (1.75) group showed minimal clinical response to RPX and a dose-related blunting of lung lesions vs CRL or IV-Cr groups. Nf protected rabbits from RPX at H10% of the equivalent IV-Cr dose. A dose-related effect was observed in clinical development of RPX disease in Nf groups. Significant reduction of RPX-induced pathological changes was observed in Nf (1.75) and IV-cidofovir groups. Results suggest that inhalable Nf may be a viable antiviral for emergency PEP and should be evaluated in other models of poxviral disease (e.g., MPX in nonhuman primates). Results of these studies will establish the relative safety and preclinical efficacy of reformulated cidofovir as a viable antiviral therapeutic against smallpox.