DEVELOPMENT OF DRUGS FOR CRYPTOSPORIDIUM INFECTION

目前治疗与艾滋病相关的机会性感染的治疗方法 获得性免疫缺陷综合症(AIDS)要么剧毒， 极其昂贵或略微有效的。因为这些感染 在艾滋病患者中产生显著的发病率和死亡率， 国家过敏和传染病研究所促进发现 和开发治疗艾滋病相关疾病的新疗法 机会性感染。这包括为以下项目提供合同资源 发现和开发潜在的新药，并进行疗效 在动物模型中的评估，这是药物批准的关键组成部分 进程。目前还没有推荐的治疗方法来治疗感染 微小隐孢子虫，部分原因是缺乏体外培养 适用于药物评价的系统和小动物模型。 该项目的第一阶段将支持三个机构制定 体外和体内测试系统。此后，在该计划的第二阶段， 将从这些机构中选择一个或多个机构来应用其系统 对潜在新药治疗的疗效进行评估 隐孢子虫。培养系统和动物模型是通过 因此，这些合同将为NIAID提供必要的资源 为研究人员发起的药物发现提供关键支持， 通过示范刺激私营部门对化合物的赞助 疗效，并选择最佳候选药物进行临床试验。 上述合同的第一阶段将使SCID鼠标适用于 体内筛选治疗隐孢子虫感染的候选药物。 评价药理作用的标准包括：卵囊 脱落、组织定植(分布和强度)和临床 有征兆。SCID小鼠模型将进一步适用于评估 使用1)预防模型、2)慢性模型的4级分析方案 模型，3)晚期/播散模型，以及4)复发/复发 模特。如果被选中参与该计划的第二阶段，承包商将1) 系统地将他们的动物模型应用于药物评价2)开发 一种可重现的、定量的微小隐孢子虫体外培养模型，以及 3)应用培养试验初步筛选化合物，以便进一步 测试-在SCID模型中。

Current therapies to treat opportunistic infections associated with the Acquired Immunodeficiency Syndrome (AIDS) are either highly toxic, extremely expensive or marginally effective. Since these infections produce significant morbidity and mortality in patients with AIDS, the National Institute of Allergy and Infectious Diseases facilitates discovery and development of novel therapies for the treatment of AIDS-related opportunistic infections. This includes providing contract resources for identifying and developing potential new drugs, and conducting efficacy evaluations in animal models, a critical component in the drug approval process. At present there is no recommended therapy for infection with Cryptosporidium parvum, in part, because of the lack of in vitro culture systems and small animal models that are suitable for drug evaluations. Phase 1 of this project will support three agencies in the development of in vitro and in vivo test systems. Thereafter in Phase 2 of the program, one or more of these agencies will be selected to apply their systems toward evaluating the efficacy of potential new drugs against Cryptosporidium. The culture systems and animal models developed through these contracts will therefore provide NIAID with the necessary resources to provide critical support for investigator-initiated drug discovery, to stimulate private sector sponsorship of compounds with demonstrated efficacy, and to select the best drug candidates for clinical trials. Phase 1 of the contract indicated above will adapt the SCID mouse for in vivo screening of candidate therapies against Cryptosporidium infection. Criteria for evaluating the impact of pharmacologic agents include: oocyst shedding, tissue colonization (distribution and intensity) and clinical signs. The SCID mouse model will be further adapted to evaluate agents in a 4-tiered assay protocol employing 1) a prophylactic model, 2) a chronic model, 3) a terminal/disseminated model, and 4) a relapsing/recurrent model. If selected for Phase 2 of the program, the contractor will 1) systematically apply their animal model toward drug evaluations 2) develop a reproducible, quantitative model of C. parvum cultivation in vitro, and 3) apply the culture assays to initially screen compounds for further testing-in the SCID model.