Novel Model to Predict Safety and Efficacy of Microbicides

预测杀菌剂安全性和功效的新模型

• 批准号: 7155967
• 负责人: GREGORY A. PRINCE
• 金额: $ 33.62万
• 依托单位: VIRION SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-19 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155967
• 关键词: Rodentias; antiinfective agents; human; infection; local antiinfective agents; model; topical drug application

DESCRIPTION (provided by applicant): Genital herpes is 1 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 (1) 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.

描述（由申请人提供）：生殖器疱疹是全世界最普遍的性传播感染（STI）中的1种，与大量发病有关。生殖器疱疹作为公共卫生威胁的影响由于其流行病学与艾滋病毒的协同作用而受到扩大。流行病学研究一致地表明，生殖器疱疹感染增加了艾滋病毒传播和获取的风险。生殖器疱疹的患病率不断增加，临床发作的频繁复发，无症状脱落的高频以及HSV与HIV传播的关联突出了迫切需要对两种病毒风险的人群的控制措施。一（1）个预防策略是局部菌皮的开发，即旨在进行阴道用途的自我管理剂，以防止STI。局部杀菌剂开发的目标是，它们是安全，负担得起的，有效的，抗HIV，HSV和其他性传播感染，并且在生殖道分泌的存在下稳定。局部杀菌剂临时发展的关键组成部分是评估反映人类疾病的小动物模型中的安全性和功效。大多数用于生殖器疱疹的动物研究都是使用鼠或豚鼠模型进行的。但是，这两个都有重大局限性。我们最近发现，棉花大鼠是与实验室小鼠和大鼠不同的家族中的一种常见的新世界啮齿动物，它提供了一种潜在的人类生殖器疾病模型。该模型的显着特征是，阴道感染不需要激素操纵，动物从原发性感染中恢复过来，但容易出现模仿人类疾病的自发临床复发，并且通过对候选局部杀伤剂Pro2000进行预处理而阻止了感染。其他优点包括研究对HSV和对菌皮的粘膜反应的可用性，与地塞米松在实验中诱导重新激活的能力，研究垂直和横向传播的潜力以及将棉花大鼠作为与其他STI的共同感染模型开发棉鼠的可能性。因此，该STTR应用的I期目标的目标是优化棉花大鼠作为模型，以评估局部杀菌剂的有效性和安全性，以防止HSV的性或围产期传播。实现此目标的具体目的是：（i）评估棉花大鼠作为反映人类疾病的生殖器疱疹感染模型。要测试的假设是，棉花大鼠将作为研究原发疱疹感染，临床和无症状复发的模型，以及水平（女性对男女或男性或男女）以及垂直（伴生的母亲到女性到女性）的传播； （ii）确定棉花大鼠是否会提供针对HSV和安全性的杀菌剂有效性的替代标记。阴道杀菌剂的临床前发展的主要差距是缺乏替代标记物来预测阴道杀菌剂的功效和安全性。我们假设棉鼠将填补这一利基。生殖器疱疹感染是最普遍的性传播感染之一，是艾滋病毒/艾滋病流行病中的主要共同因素。迫切需要防止两种病原体传播和获取的新型策略，例如安全有效的阴道杀菌剂的发展。这种新型药物的开发的主要局限性是缺乏预测安全性和有效性的小动物模型。初步研究表明，棉花大鼠将填补这一利基。该STTR应用I期I期的目标是优化棉花大鼠作为模型，以评估局部杀菌剂的有效性和安全性，以防止HSV的性或产前传播。