Nanomedicine approaches for prevention of inflammation-induced preterm birth

预防炎症引起的早产的纳米医学方法

基本信息

批准号：
10406669
负责人：
IRINA BURD
金额：
$ 7.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-13 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406669
关键词：
37 weeks gestation Address Birth Brain Injuries Caproates Cell Culture Techniques Cells Cerebral Palsy Cognitive Data Development Dose Drug Combinations Drug Delivery Systems Drug Kinetics Excipients Exposure to Gene Expression Gene Expression Profiling Histone Deacetylase Inhibitor Human Hydroxyprogesterone Impaired cognition Infant Care Inflammation Inflammatory Inflammatory Response Pathway Injections Intravaginal Administration Label Lead Measures Mucous Membrane Mus Myometrial Outcome Penetration Perinatal Brain Injury Pharmaceutical Preparations Pregnancy Premature Birth Premature Labor Prevention Prevention approach Progesterone Recording of previous events Route Schizophrenia Signal Transduction Synthetic Progestogens Therapeutic Effect Tissues Tocolytic Agents Toxic effect Uterine Contraction Uterus Vagina Woman autism spectrum disorder delayed birth drug candidate drug market effective therapy fetal inflammatory response syndrome in vitro Assay infant death innovation intrauterine inflammation kinase inhibitor mouse model nanomedicine neurobehavioral premature prevent pup receptor expression reproductive

37 weeks gestation Address Birth Brain Injuries Caproates Cell Culture Techniques Cells Cerebral Palsy Cognitive Data Development Dose Drug Combinations Drug Delivery Systems Drug Kinetics Excipients Exposure to Gene Expression Gene Expression Profiling Histone Deacetylase Inhibitor Human Hydroxyprogesterone Impaired cognition Infant Care Inflammation Inflammatory Inflammatory Response Pathway Injections Intravaginal Administration Label Lead Measures Mucous Membrane Mus Myometrial Outcome Penetration Perinatal Brain Injury Pharmaceutical Preparations Pregnancy Premature Birth Premature Labor Prevention Prevention approach Progesterone Recording of previous events Route Schizophrenia Signal Transduction Synthetic Progestogens Therapeutic Effect Tissues Tocolytic Agents Toxic effect Uterine Contraction Uterus Vagina Woman autism spectrum disorder delayed birth drug candidate drug market effective therapy fetal inflammatory response syndrome in vitro Assay infant death innovation intrauterine inflammation kinase inhibitor mouse model nanomedicine neurobehavioral premature prevent pup receptor expression reproductive

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项目摘要

PROJECT SUMMARY Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Here, we focus on the most common cause of PTB, inflammation. Maternal inflammation triggers a pro-inflammatory cytokine response that can also lead to fetal inflammatory response syndrome and perinatal brain injury. Brain injury leads to a spectrum of adverse neurobehavioral outcomes, including cerebral palsy, autism, schizophrenia, and cognitive delay among others. The only approved drug for prevention of PTB is the synthetic progestin hydroxyprogesterone caproate (OHPC) dosed systemically as weekly injections in women with a singleton pregnancy with a history of singleton spontaneous PTB, and a recently failed confirmatory study has led to calls for the FDA to withdraw the drug from the market. For women that are already in preterm labor, off-label tocolytics (anti-contraction medications) may be given to slow uterine contractions, but this typically only delays birth for a few days. New, effective treatments for preventing PTB are desperately needed. Further, the vaginal route of administration is underexplored but highly promising; vaginally absorbed drug is preferentially transported to the uterus. We have demonstrated that by increasing mucosal drug penetration and eliminating hypertonic excipients that cause local toxicity, increased drug delivery to target reproductive tissues can be achieved. In the setting of intrauterine inflammation, we have observed that combining vaginal progesterone (P4) with drugs that favor non-laboring states of P4 receptor and gene expression, such as histone deacetylase inhibitors (HDACi), provides a significant increase in dams that go on to deliver live pups. In contrast, dosing the same drug combination systemically or injecting the approved product OHPC had no therapeutic effect. Analysis of gene expression changes suggest that quiescing myometrial activity was key, and we have confirmed that the myometrial tissue levels of P4 and HDACi measured after vaginal combination delivery in mice were also the most effective in preventing human myometrial cell contractility. Importantly, preliminary neurobehavioral analysis of pups born after exposure to intrauterine inflammation followed by vaginal P4/HDACi suggests that development occurred similar to pups that had not been exposed to intrauterine inflammation. Herein, we propose studies that use in vitro assays for assessing the potential of kinase inhibitors as a drug class for repurposing in PTB prevention. Candidate drugs will be screened for inhibition of myometrial contractility in human myometrial cell culture, and downstream effects on inflammatory signaling will be assessed. The most effective drugs will then be formulated for vaginal administration and incorporation into studies assessing pharmacokinetics and efficacy in an inflammation-induced mouse model of PTB.

项目摘要早产（PTB）或妊娠37周之前的出生是婴儿死亡的第二大原因我们在2017年。每年，超过260亿美元用于治疗和护理婴儿，而不是考虑到发展和认知障碍的终生影响。在这里，我们最关注 PTB的常见原因，炎症。母体炎症会触发促炎性细胞因子反应这也可能导致胎儿炎症反应综合征和围产期脑损伤。脑损伤导致不良神经行为结局的范围，包括脑瘫，自闭症，精神分裂症和认知延迟。预防PTB的唯一批准的药物是合成孕激素羟化甲状酸酯（OHPC）全身服用，每周注射妇女具有单身人士自发PTB病史的怀孕以及最近失败的确认性研究导致了呼吁FDA从市场上撤出该药物。对于已经从事早产的女性，标签外可以给子宫收缩缓慢的溶剂剂（抗收缩药），但这通常仅延迟出生几天。迫切需要进行新的，有效的预防PTB治疗方法。此外，阴道行政途径尚未得到充实，但很有希望。阴道吸收的药物优先运送到子宫。我们已经证明，通过增加粘膜药物渗透并消除引起局部毒性的高渗性摄取因素，药物递送到目标生殖组织的递送可能是成就了。在宫内炎症的情况下，我们观察到结合阴道孕酮（p4）有利于P4受体和基因表达的非标记态的药物，例如组蛋白脱乙酰基酶抑制剂（HDACI）可显着增加用于提供活幼崽的水坝。在对比，系统地给予相同的药物组合或注入批准的产品OHPC没有治疗效果。基因表达变化的分析表明，戒除肌层活性是关键，我们已经证实了阴道组合后测量的P4和HDACI的子宫肌层组织水平小鼠的递送也是预防人肌层细胞收缩力的最有效的。重要的是，暴露于子宫内炎症后出生的幼崽的初步神经行为分析，然后阴道P4/HDACI表明发育发生类似于未暴露于宫内炎症。在此，我们提出了使用体外测定法来评估潜力的研究激酶抑制剂作为预防PTB的药物类别。候选药物将被筛选抑制人肌层细胞培养中的肌层收缩力，以及对炎症的下游影响信令将被评估。然后，最有效的药物将用于阴道给药和纳入评估炎症诱导的小鼠模型中药代动力学和功效的研究 PTB。