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: 8265110
• 负责人: Adam Jonathan Ratner
• 金额: $ 25.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265110
• 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

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. PUBLIC HEALTH RELEVANCE: Reproductive tract infections (RTI) are a major cause of disease in pregnant women and newborns. In this proposal, we will perform preclinical evaluation of a new non-antibiotic strategy for prevention of two of the most common RTI in pregnancy. We will study both the biological and the psychological/behavioral impact of such a strategy.

描述（由申请人提供）：在怀孕期间，生殖道感染（RTI）特别相关，对孕产妇和新生儿健康具有重要意义。细菌性阴道病和B组链球菌均与生物膜形成和阴道粘膜表面的长期定植有关。我们发现，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（新生儿早期发作败血症的主要原因）形成了含有细胞外DNA的生物膜，并且对源自源自dnase的活性敏感。因此，我们假设阴道内DNase凝胶可以降低妊娠晚期的其他RTI的风险。我们的总体目的是通过制定铅候选DNase凝胶进行体外和体内测试，并利用我们在杀菌剂可接受性研究中的经验来确定现实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分阶段创新研究中，R21阶段将着重于DNase凝胶原型的制定以及对使用体外和体内模型以及开发行为工具的妊娠相关RTI的功效评估，以研究孕妇的微生物可接受性。在R33阶段，我们将优化铅凝胶候选者，在体内进行扩展的功效和毒理学研究，并使用我们的行为工具来研究孕妇的本地和全国代表性人群。在这两个阶段的结论中，我们将完成对DNase凝胶预防两个重要RTI怀孕的详细临床前评估，并将对对实施这种策略重要的行为因素进行评估。如果合适的凝胶能够以体内功效和可接受的毒理学特征来结束R33阶段的结论，我们将继续以人类测试的最终目标来实现。 公共卫生相关性：生殖道感染（RTI）是孕妇和新生儿疾病的主要原因。在此提案中，我们将对一种新的非抗生素策略进行临床前评估，以预防怀孕中最常见的两种RTI。我们将研究这种策略的生物学和心理/行为影响。