DNase For Prevention Of Reproductive Tract Infections In Pregnancy

DNase 用于预防妊娠期生殖道感染

• 批准号: 8812495
• 负责人: Adam Jonathan Ratner
• 金额: $ 56.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812495
• 关键词: Attitude; Bacterial Vaginosis; Behavior assessment; Behavioral; Biological; DNA; Deoxyribonucleases; Development; Disease; Dose; Drug Formulations; Effectiveness; Gardnerella vaginalis; Gel; Goals; Health; Human; In Vitro; Lead; Microbial Biofilms; Modeling; Neonatal; Newborn Infant; Phase; Population; Predisposition; Pregnancy; Pregnant Women; Prevalence; Prevention; Prevention strategy; Questionnaires; Reproductive Tract Infections; Risk; Schedule; Sepsis; Severities; Streptococcus Group B; Surface; System; Testing; Toxic effect; Toxicology; Vagina; aqueous; base; chemical stability; demographics; early onset; efficacy evaluation; experience; extracellular; in vitro Model; in vitro testing; in vivo; in vivo Model; innovation; instrument; microbicide; pathogen; preclinical evaluation; pregnancy prevention; prevent; prototype; psychologic

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.

DNase 用于预防妊娠期生殖道感染 抽象的 生殖道感染 (RTI) 在怀孕期间尤其重要， 对孕产妇和新生儿健康具有重要影响。两者都是细菌性阴道病 B 族链球菌与生物膜形成和长期 RTI 相关 阴道粘膜表面定植。我们发现加德纳菌 阴道菌（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（新生儿早发败血症的主要原因） 生物膜含有细胞外 DNA，对外源性物质的活性敏感 脱氧核糖核酸酶。因此，我们假设阴道内 DNase 凝胶可以降低以下风险： 这些以及妊娠晚期可能发生的其他 RTI。我们的总体目标是严格 通过配制用于体外和体内的主要候选 DNase 凝胶来评估这一假设 体内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策略的潜在障碍 怀孕。在拟议的连续 R21/R33 分阶段创新研究中，R21 该阶段将重点关注 DNase 凝胶原型的配制和功效评估 使用体外和体内模型对抗与妊娠相关的 RTI 并开发 研究孕妇对杀微生物剂可接受性的行为工具。在R33中 阶段，我们将优化先导凝胶候选物，扩大功效并 体内毒理学研究，并使用我们的行为仪器进行本地研究和 具有全国代表性的孕妇人口。两人的结论是 阶段，我们将完成 DNase 凝胶的详细临床前评估 预防怀孕期间两种重要的 RTI 并将进行评估 行为因素对于实施此类策略很重要。如果有合适的凝胶 进展到 R33 阶段的结论，具有体内功效和可接受的 毒理学概况，我们将朝着人体测试的最终目标前进。