DNase For Prevention Of Reproductive Tract Infections In Pregnancy

DNA酶在预防妊娠生殖道感染中的作用 摘要 生殖道感染(RTI)在妊娠期和 对产妇和新生儿健康有重要影响。两种细菌性阴道病 B群链球菌与生物被膜形成和长期感染相关 阴道粘膜表面的定植。我们发现加德纳氏菌和加德纳氏菌 阴道(细菌性阴道病期间阴道微生物区系的主要组成部分)和 B组链球菌(新生儿早发性败血症的主要原因)形式 含有胞外DNA并对外源DNA活性敏感的生物膜 DNA酶。因此，我们假设阴道内注射脱氧核糖核酸酶凝胶可以降低罹患 这些和可能的其他RTI在妊娠晚期。我们的总体目标是严格执行 评估这一假说，通过制定一个领先的候选DNA酶凝胶在体外和 活体测试，并利用我们在杀菌剂可接受性研究方面的经验 确定在现实世界中使用这种预防性战略的潜在障碍 怀孕了。在拟议的R21/R33阶段性创新研究中，R21 阶段将侧重于DNA酶凝胶原型的配制和疗效评估 利用体外和体内模型抗与妊娠相关的RTI及其研究进展 研究杀微生物剂在孕妇中可接受性的行为工具。在R33公路上 阶段，我们将优化候选铅凝胶，进行扩大疗效和 活体毒理学研究，并使用我们的行为仪器在当地和 具有全国代表性的孕妇群体。在两本书的结束语中 阶段，我们将完成对DNase凝胶的详细临床前评估 预防孕期两个重要的RTI，并将进行一项评估 对实施这一战略很重要的行为因素。如果一种合适的凝胶 具有体内疗效和可接受的R33期结束的研究进展 毒理学简介，我们将继续推进人体测试的最终目标。

DNase for prevention of reproductive tract infections in pregnancy ABSTRACT 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.