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

在美国，十分之一的婴儿是早产的。怀孕越早，婴儿出生的时间越长 他们可能会有较长的住院时间，以及严重的健康并发症，如呼吸道并发症 窘迫综合征、坏死性小肠结肠炎、耳聋、视力问题和脑性瘫痪。母性压力是一种 早产的风险因素已经确定，最近使用母体应激小鼠模型的研究强调了 应激反应蛋白FKBP51在促进早产中的作用。先前的研究表明，压力 促进FKBP51的表达。因此，FKBP51与蜕膜细胞中的孕激素受体结合 母胎界面，降低了细胞核中孕酮受体的活性，导致功能性 黄体酮停用引发人类分娩和分娩的黄体酮的退出。重要的是，这种新的分子途径 可被15-脱氧前列腺素J2(15dPGJ2，15dPGJ2)阻断，恢复孕激素受体的活性 在体外和体内。因此，FKBP51靶向治疗作为一种安全有效的治疗策略具有巨大的潜力。 防止早产。因为目前还没有预防早产的药物策略， 达雷生物科学公司与南佛罗里达大学合作，旨在严格展示 以FKBP51为靶点改善妇女产科治疗选择的可行性。目标1的工作重点是 使用临床相关的人蜕膜细胞培养模型验证FKBP51作为新的药物靶点，选择 联合15dPGJ2和孕激素的治疗策略，并评估其下游 治疗的生物效应。目标2的重点是证明15dPGJ2在体内的安全性和有效性 孕激素联合疗法在先前证实的母亲应激诱导的妊娠维持中的作用 早产小鼠模型。其目标是证明妊娠长度在统计上显著增加。 应激动物与未经处理的应激对照动物经处理(S)。该项目具有重要的翻译和 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 到第二阶段的IND使能研究。

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.