DNase For Prevention Of Reproductive Tract Infections In Pregnancy

描述（由申请人提供）：生殖道感染（RTI）与妊娠期特别相关，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RTI。我们已经发现，阴道加德纳菌（细菌性阴道病期间阴道微生物群的主要成分）和B组链球菌（新生儿早发性脓毒症的主要原因）形成含有细胞外DNA的生物膜，并且对外源性DNA酶的活性敏感。因此，我们假设阴道内DNA酶凝胶可以降低这些风险和潜在的其他RTI在怀孕后期。我们的总体目标是严格评估这一假设，通过制定一个领先的候选人DNA酶凝胶在体外和体内测试，并利用我们在杀微生物剂的可接受性研究的经验，以确定潜在的障碍，在怀孕期间的实际使用这样的预防策略。在拟议的R21/R33阶段性创新研究中，R21阶段将重点关注DNA酶凝胶原型的配制，并使用体外和体内模型评价对妊娠相关RTI的疗效，以及开发行为工具以研究孕妇中杀微生物剂的可接受性。在R33阶段，我们将优化先导凝胶候选物，在体内进行扩大的疗效和毒理学研究，并使用我们的行为工具研究当地和全国有代表性的孕妇群体。在这两个阶段结束时，我们将完成一个详细的临床前评估的DNA酶凝胶预防两个重要的RTI在怀孕期间，并将进行评估的行为因素的重要实施这样一个战略。如果一种合适的凝胶进入R33阶段，具有体内疗效和可接受的毒理学特征，我们将继续推进人体试验的最终目标。

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.