Therapeutic targeting of FKBP51 for the prevention of stress-induced preterm birth

FKBP51 预防应激性早产的治疗靶点

基本信息

批准号：
10758367
负责人：
DAVID R FRIEND
金额：
$ 38.5万
依托单位：
DARE BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758367
关键词：
AKR1C1 Affect Animals Binding Biological Biological Sciences Birth Birth Rate Birth Weight Black race Brain Cell Culture Techniques Cell Line Cell Nucleus Cells Cerebral Palsy Clinical Collaborations Combined Modality Therapy Complex Corticosterone Cytoplasm Data Decidual Cell Development Discipline of obstetrics Disease Dose Economic Burden Endometrium Enzymes FDA approved FK506 binding protein 5 Face Family Fetus Florida Gastrointestinal tract structure Goals Health Hearing High Risk Woman Human Hydroxysteroid Dehydrogenases In Vitro Induced Labor Infant Mortality Injectable Intraperitoneal Injections Knockout Mice Laboratories Length Length of Stay Ligands Link Litter Size Lung Marketing Maternal-Fetal Exchange Measures Mediating Messenger RNA Metabolism Modeling Molecular Mothers Mus Necrotizing Enterocolitis Newborn Infant Nuclear Pathway interactions Phase Phase I Clinical Trials Placebos Pregnancy Pregnancy Maintenance Pregnant Women Premature Birth Premature Infant Prevention Prevention approach Prevention strategy Progesterone Progesterone Receptors Progestins Prophylactic treatment Prostaglandins Proteins RU-5020 Recommendation Reporting Resistance Risk Risk Factors Role Route Safety Schools Serum Small Business Technology Transfer Research Steroids Stress Survivors Synthetic Progestogens Therapeutic Treatment Efficacy United States Universities Uterus Vagina Vision Wild Type Mouse Withdrawal Woman Work biological adaptation to stress clinically relevant deafness efficacy testing improved improved outcome in vivo infant outcome inflammatory marker inhibitor maternal stress maternal weight mouse model new therapeutic target novel novel strategies novel therapeutic intervention pharmacologic pregnant premature prevent primary endpoint pup research and development respiratory distress syndrome side effect skills social standard of care therapeutic target treatment effect treatment group treatment strategy validation studies

项目摘要

In the United States, one in ten babies is born prematurely. The earlier in pregnancy a baby is born, the more likely they will have an extended hospital stay, as well as serious health complications such as respiratory distress syndrome, necrotizing enterocolitis, deafness, vision problems and cerebral palsy. Maternal stress is a well-established risk factor for preterm birth, and recent studies using a mouse model of maternal stress highlight the role of a stress response protein, FKBP51, in promoting preterm birth. Prior work demonstrates that stress boosts FKBP51 expression. Consequently, FKBP51 binds to progesterone receptors in decidual cells at the maternal-fetal interface, reducing progesterone receptor activity in the nucleus, resulting in the functional withdrawal of progesterone that triggers labor and birth in humans. Importantly, this novel molecular pathway can be blocked by 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), restoring the activity of progesterone receptors in vitro and in vivo. Thus, therapeutic targeting of FKBP51 has great potential as a safe and effective strategy to prevent preterm birth. Because there exist no pharmacological strategies for the prevention of preterm birth, Daré Bioscience, in collaboration with the University of South Florida, aims to rigorously demonstrate the feasibility of targeting FKBP51 to improve obstetric treatment options for women. Work in Aim 1 is focused on validating FKBP51 as a novel drug target using clinically-relevant human decidual cell culture models, selecting a therapeutic strategy that combines 15dPGJ2 with delivery of a progestin, and evaluating the downstream biological effects of treatment. The focus of Aim 2 is to demonstrate the in vivo safety and efficacy of 15dPGJ2 plus progestin combination therapy for pregnancy maintenance in a previously validated maternal stress induced mouse model of preterm birth. The goal is to demonstrate a statistically significant increase in gestational length by treatment(s) in stressed animals vs. untreated stressed controls. This project has significant translational and commercial potential because it will provide the necessary proof-of-concept data to advance a treatment strategy to Phase II IND-enabling studies.

在美国，十分之一的婴儿早产。怀孕期间出生的婴儿越早。他们可能会延长住院时间，并出现严重的健康并发症，例如呼吸道疾病应激综合征、坏死性小肠结肠炎、耳聋、视力问题和脑瘫是产妇应激的一种。已确定的早产危险因素，以及最近使用孕产妇压力小鼠模型进行的研究强调压力反应蛋白 FKBP51 在促进早产中的作用先前的研究表明压力。经测试，FKBP51 与蜕膜细胞中的孕酮受体结合。母胎界面，降低细胞核中孕酮受体的活性，导致功能性重要的是，这种新的分子途径会引发人类分娩。可以被 15-脱氧-Δ12,14-前列腺素 J2 (15dPGJ2) 阻断，恢复孕激素受体的活性因此，FKBP51 的治疗靶向作为一种安全有效的策略具有巨大的潜力。预防早产因为没有预防早产的药物策略， Daré Bioscience 与南佛罗里达大学合作，旨在严格证明目标 1 的工作重点是针对 FKBP51 改善女性产科治疗选择的可行性。使用临床相关的人类蜕膜细胞培养模型验证 FKBP51 作为新药物靶点，选择将 15dPGJ2 与孕激素递送相结合的治疗策略，并评估下游目标 2 的重点是证明 15dPGJ2 的体内安全性和有效性。加上孕激素联合治疗，用于先前验证的母亲应激诱发的妊娠维持早产小鼠模型的目标是证明妊娠长度在统计学上显着增加。通过对应激动物进行治疗与未治疗的应激对照进行比较，该项目具有显着的转化和效果。商业潜力，因为它将提供必要的概念验证数据来推进治疗策略到第二阶段 IND 启用研究。