DNase For Prevention Of Reproductive Tract Infections In Pregnancy

描述(由申请人提供)：生殖道感染(RTI)在妊娠期特别相关，对孕产妇和新生儿健康具有重要影响。细菌性阴道病和B组链球菌都是与生物膜形成和阴道粘膜表面长期定植相关的呼吸道感染。我们发现，阴道加德纳氏菌(细菌性阴道病时阴道微生物区系的主要组成部分)和B群链球菌(新生儿早发性脓毒症的主要原因)都形成了含有胞外DNA的生物膜，并且对外源DNA酶的活性敏感。因此，我们假设，阴道内DNA酶凝胶可以降低妊娠晚期这些和潜在的其他RTI的风险。我们的总体目标是严格评估这一假设，方法是制定一种用于体外和体内测试的主要候选DNA酶凝胶，并利用我们在杀菌剂可接受性研究方面的经验来确定在怀孕期间使用这种预防策略的潜在障碍。在拟议的R21/R33阶段性创新研究中，R21阶段将专注于DNase凝胶原型的制定和使用体外和体内模型评估与妊娠相关的RTI的疗效，并开发行为工具来研究孕妇对杀菌剂的接受程度。在R33阶段，我们将优化候选铅凝胶，进行体内扩大的疗效和毒理学研究，并使用我们的行为仪器研究当地和全国具有代表性的孕妇群体。在两个阶段的结束时，我们将完成用于预防妊娠期间两个重要RTI的DNase凝胶的详细临床前评估，并将对实施此类策略的重要行为因素进行评估。如果一种合适的凝胶在体内的有效性和可接受的毒理学特征下进入R33阶段的结束，我们将继续推进人体测试的最终目标。 公共卫生相关性：生殖道感染(RTI)是导致孕妇和新生儿患病的主要原因。在这项提案中，我们将对一种新的非抗生素策略进行临床前评估，以预防妊娠期最常见的两种RTI。我们将研究这种策略的生物学影响和心理/行为影响。

DESCRIPTION (provided by applicant): Reproductive tract infections (RTI) are of particular relevance during pregnancy and have important implications for maternal and neonatal health. Both bacterial vaginosis and group B Streptococcus are RTI associated with biofilm formation and long-term colonization of the vaginal mucosal surface. We have found that both Gardnerella vaginalis (the major constituent of the vaginal microbiota during bacterial vaginosis) and group B Streptococcus (the leading cause of early-onset sepsis in newborns) form biofilms that contain extracellular DNA and are sensitive to the activity of exogenous DNase. Thus, we hypothesize that an intravaginal DNase gel could decrease the risk of these and potentially other RTI in late pregnancy. Our overall goal is to rigorously evaluate this hypothesis by formulating a lead candidate DNase gel for in vitro and in vivo testing and by leveraging our experience in microbicide acceptability studies to determine potential barriers to the real-world use of such a preventive strategy during pregnancy. In the proposed sequential R21/R33 phased innovation study, the R21 phase will focus on formulation of DNase gel prototypes and evaluation of efficacy against RTI relevant to pregnancy using in vitro and in vivo models and on developing behavioral instruments to study microbicide acceptability in pregnant women. In the R33 phase, we will optimize the lead gel candidate, perform expanded efficacy and toxicology studies in vivo, and use our behavioral instrument to study locally and nationally representative populations of pregnant women. At the conclusion of the two phases, we will have completed a detailed preclinical evaluation of a DNase gel for the prevention of two important RTI in pregnancy and will have performed an assessment of behavioral factors important to the implementation of such a strategy. If a suitable gel advances to the conclusion of the R33 phase with in vivo efficacy and an acceptable toxicologic profile, we will move forward with the eventual goal of human testing. PUBLIC HEALTH RELEVANCE: Reproductive tract infections (RTI) are a major cause of disease in pregnant women and newborns. In this proposal, we will perform preclinical evaluation of a new non-antibiotic strategy for prevention of two of the most common RTI in pregnancy. We will study both the biological and the psychological/behavioral impact of such a strategy.