DNase For Prevention Of Reproductive Tract Infections In Pregnancy

描述（由申请人提供）：生殖道感染（RTI）在怀孕期间特别相关，对孕产妇和新生儿健康有重要影响。细菌性阴道病和B族链球菌都是与阴道粘膜表面生物膜形成和长期定植有关的RTI。我们发现阴道加德纳菌（细菌性阴道病期间阴道微生物群的主要成分）和B群链球菌（新生儿早发性败血症的主要原因）形成的生物膜含有细胞外DNA，并且对外源性DNA酶的活性敏感。因此，我们假设阴道内dna酶凝胶可以降低妊娠后期这些和潜在的其他RTI的风险。我们的总体目标是通过制定用于体外和体内测试的主要候选dna酶凝胶，并利用我们在杀微生物剂可接受性研究方面的经验来确定在怀孕期间实际使用这种预防策略的潜在障碍，从而严格评估这一假设。在拟议的顺序R21/R33阶段创新研究中，R21阶段将重点研究DNase凝胶原型的制定和体外和体内模型对妊娠相关RTI的疗效评估，以及开发行为工具来研究孕妇对杀微生物剂的接受程度。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具有代表性的孕妇人群。在这两个阶段结束时，我们将完成对DNase凝胶预防妊娠期两种重要RTI的详细临床前评估，并对实施这种策略的重要行为因素进行评估。如果一种合适的凝胶在R33期结束时具有体内功效和可接受的毒理学特征，我们将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.