Novel Model to Predict Safety and Efficacy of Microbicides

描述(申请人提供)：生殖器疱疹是全世界最流行的性传播感染(STI)之一，与相当大的发病率有关。生殖器疱疹作为公共卫生威胁的影响被放大，因为它与艾滋病毒具有流行病学协同效应。流行病学研究一贯表明，生殖器疱疹感染增加了艾滋病毒传播和感染的风险。生殖器疱疹的流行日益增加，临床发作频繁，无症状脱落的频率很高，单纯疱疹病毒与艾滋病毒传播的联系突出表明，迫切需要在有这两种病毒风险的人群中采取控制措施。一种预防策略是开发局部杀微生物剂，这是一种用于阴道使用的自我给药药物，用于预防STI。开发局部杀微生物剂的目标是安全、负担得起、对艾滋病毒、单纯疱疹病毒和其他性传播感染有效，并且在生殖道分泌物存在时稳定。局部杀微生物剂临床前开发的一个关键组成部分是在反映人类疾病的小动物模型中评估安全性和有效性。大多数生殖器疱疹的动物研究都是使用小鼠或豚鼠模型进行的。然而，这两种方法都有很大的局限性。我们最近发现，棉鼠是一种常见的新大陆啮齿类动物，与实验室老鼠和大鼠不同，它提供了一种潜在的生物学上更优越的人类生殖器疾病模型。该模型的显著特点是，阴道感染不需要激素调节，动物从初次感染中恢复，但容易出现模仿人类疾病的自发临床复发，通过使用候选局部杀菌剂PRO2000进行预处理来预防感染。其他优势包括研究HSV和杀微生物剂对粘膜反应的试剂的可用性，地塞米松实验诱导再激活的能力，研究垂直和水平传播的潜力，以及将棉花鼠发展为与其他STI合并感染的模型的可能性。因此，这一STTR应用的第一阶段的目标是优化棉鼠作为评估局部杀微生物剂预防HSV性传播或围产期传播的有效性和安全性的模型。实现这一目标的具体目标是：(I)评估棉花鼠作为反映人类疾病的生殖器疱疹感染的模型。要测试的假设是，棉鼠将作为研究原发疱疹感染、临床和无症状复发以及水平传播(女性对男性或男性对女性)和垂直(产中母亲对后代)传播的模型；(Ii)确定棉花老鼠是否将提供抗单纯疱疹病毒微生物剂有效性和安全性的替代标记物。阴道杀微生物剂临床前发展的一个主要差距是缺乏替代标记物来预测阴道杀微生物剂的有效性和安全性。我们假设棉花鼠将填补这一利基。生殖器疱疹感染是最普遍的性传播感染之一，也是艾滋病毒/艾滋病流行的一个主要辅助因素。迫切需要新的战略来预防这两种病原体的传播和获得，例如开发安全有效的阴道杀菌剂。这类新药开发的一个主要限制是缺乏小动物模型来预测安全性和有效性。初步研究表明，棉鼠将填补这一利基。这一STTR应用的第一阶段的目标是优化棉鼠作为评估局部杀菌剂预防HSV性传播或产前传播的有效性和安全性的模型。

DESCRIPTION (provided by applicant): Genital herpes is one of the most prevalent sexually transmitted infections (STI) worldwide and is associated with substantial morbidity. The impact of genital herpes as a public health threat is amplified because of its epidemiologic synergy with HIV. Epidemiological studies consistently demonstrate that genital herpes infection increases the risk of HIV transmission and acquisition. The increasing prevalence of genital herpes, the frequent recurrence of clinical episodes, the high frequency of asymptomatic shedding and the association of HSV with HIV transmission highlight the urgent need for control measures in populations at risk for both viruses. One preventative strategy is the development of topical microbicides, self-administered agents designed for vaginal use to prevent STI. Goals for the development of topical microbicides are that they be safe, affordable, effective against HIV, HSV, and other STI, and stable in the presence of genital tract secretions. A key component to the pre-clinical development of topical microbicides is evaluation of safety and efficacy in small animal models that reflect human disease. Most animal studies for genital herpes have been conducted using either a murine or guinea pig model. However both of these have significant limitations. We recently found that the cotton rat, a common New World rodent in a family distinct from the laboratory mouse and rat, provides a potentially biologically superior model of human genital disease. Salient features of this model are that vaginal infection does not require hormonal manipulation, animals recover from primary infection but are prone to spontaneous clinical recurrences that mimic human disease, and infection is prevented by pretreatment with a candidate topical microbicide, PRO2000. Additional advantages include the availability of reagents to study the mucosal response to HSV and to microbicides, ability to induce reactivation experimentally with dexamethasone, the potential to study vertical and horizontal transmission, and the possibility of developing the cotton rat as a model of co-infection with other STI. Therefore, the goal of Phase I of this STTR application is to optimize the cotton rat as a model to evaluate the effectiveness and safety of topical microbicides to prevent sexual or perinatal transmission of HSV. The specific aims to achieve this goal are: (i) Evaluate the cotton rat as a model of genital herpes infection reflective of human disease. The hypothesis to be tested is that the cotton rat will serve as a model to study primary herpes infection, clinical and asymptomatic recurrences, and horizontal (female-to-male or male-to-female) and vertical (intra-partum mother-to-offspring) transmission; (ii) Determine whether the cotton rat will provide a surrogate marker of microbicide effectiveness against HSV and safety. A major gap in the preclinical development of vaginal microbicides is the absence of surrogate markers to predict both efficacy and safety of vaginal microbicides. We hypothesize that the cotton rat will fill this niche. Genital herpes infection is one of the most prevalent sexually transmitted infections and is a major co-factor in the HIV/AIDS epidemic. Novel strategies to prevent transmission and acquisition of both pathogens, such as the development of safe and effective vaginal microbicides, are urgently needed. A major limitation in the development of this novel class of drugs is the absence of a small animal model to predict safety and effectiveness. Preliminary studies indicate that the cotton rat will fill this niche. The goal of Phase I of this STTR application is to optimize the cotton rat as a model to evaluate the effectiveness and safety of topical microbicides to prevent sexual or prenatal transmission of HSV.