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: 8843772
• 负责人: Adam Jonathan Ratner
• 金额: $ 57.34万
• 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 2015-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843772
• 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.

预防妊娠生殖道感染的DNase 抽象的 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具有重要意义。两种细菌性阴道病 和B组链球菌是与生物膜形成和长期相关的RTI 阴道粘膜表面的定殖。我们发现两个Gardnerella 阴道（细菌性阴道病期间阴道菌群的主要成分）和 B组链球菌（新生儿早发败血症的主要原因）形式 含有细胞外DNA且对外源活性敏感的生物膜 DNase。因此，我们假设阴道内DNase凝胶可以降低 这些以及可能在怀孕晚期的其他RTI。我们的总体目标是严格 通过制定铅候选DNase凝胶的体外和IN来评估该假设 体内测试并利用我们在微生物剂可接受性研究中的经验 确定在现实世界中使用这种预防策略的潜在障碍 怀孕。在拟议的顺序R21/R33分阶段创新研究中，R21 阶段将集中于DNase凝胶原型的制定和疗效的评估 反对与使用体外和体内模型以及发展的RTI相关的RTI 研究孕妇的菌心可接受性的行为工具。在R33中 阶段，我们将优化铅凝胶候选者，执行扩展的功效和 体内毒理学研究，并使用我们的行为工具在本地研究和 孕妇的全国代表人群。在两者的结尾 阶段，我们将完成对DNase凝胶的详细临床前评估 预防两种重要的RTI怀孕，并将对 行为因素对于实施这种策略很重要。如果合适的凝胶 在体内功效和可接受的R33阶段结论的进步 毒理学概况，我们将以人类测试的最终目标前进。