Repurposing CRH antagonists for the treatment of endometriosis

项目总结 子宫内膜异位症是一种慢性疾病，全世界10%的育龄妇女会受到影响。不幸的是，UP 到59%的子宫内膜异位症患者对可用的治疗没有反应，并继续遭受 子宫内膜异位症相关疼痛或治疗停止后复发疼痛。因此，治疗替代方案 偏离当前的治疗重点是迫切需要的。促肾上腺皮质激素释放激素受体 类型1(CRHR1)在很大程度上是一个未被探索的目标。促肾上腺皮质激素释放激素(CRH)，它激活 CRHR1是下丘脑-垂体-肾上腺(HPA)轴中的一个关键分子，它整合了应激和 在大脑和外周组织中的内分泌反应。CRHR1在子宫内膜中含量丰富， 正如该团队先前的工作所证明的那样，卵巢和子宫内膜异位症组织的形成有一定的作用。 CRHR1拮抗剂被引入到情绪和胃肠疾病的临床试验中，几乎没有 对这些疾病有影响，但从未获得商业用途的批准。这项研究的先前工作 研究小组证明，短期使用安塔拉明治疗，这是一种CRHR1拮抗剂，经常用于临床前 实验表明，子宫内膜异位症的发生减少了30%，体重和体重减少了60% 子宫内膜异位症小泡大小。在继续这些努力的同时，总体目标是发展和 CRHR1拮抗剂商业化治疗子宫内膜异位症。研究小组最近将专注于一种化合物 专利过期，进入第二阶段临床试验，但对抑郁症、焦虑症或酒精中毒无效。至 开始讨论我们的目标时，我们设计了两个具体目标：在目标1上，我们将确定 临床相关CRHR1拮抗剂治疗子宫内膜异位症的疗效观察 伴随的疼痛。目标2将确定CRHR1拮抗剂是否影响性腺轴的周期激素 活性，与抗增殖活性无关。这两个目标都将使用成熟的 自体移植大鼠子宫内膜异位症模型，允许有效地量化和表征 子宫内膜异位小泡。完成AIMS将揭示阻止子宫内膜异位症进展的最佳干预措施 并预测与CRHR1在性腺系统中的作用直接相关的可能的作用机制。 未来的努力将集中在CRHR1拮抗如何影响生育和繁殖力，这是关键因素 申请在FDA重新进行临床测试。将CRHR1拮抗剂带入商业领域 有很强的潜力减少子宫内膜异位症患者的手术干预，导致 在医疗保健和间接成本方面节省了数千美元。研究小组已经确定了潜在的 重新调整CRHR1拮抗剂的用途，但在重新引入临床试验之前，额外的作用证据和 需要临床前的有效性。

PROJECT SUMMARY Endometriosis is a chronic condition that affects 10% of reproductive-aged women worldwide. Unfortunately, up to 59% of women with endometriosis do not respond to the available treatments and continue to suffer from endometriosis-associated pain or recurrent pain after treatment cessation. Therefore, treatment alternatives that deviate from the current therapeutic focus are urgently needed. The corticotrophin-releasing hormone receptor type 1 (CRHR1) is a largely unexplored target. Corticotropin-releasing hormone (CRH), which activates the CRHR1, is a critical molecule in the hypothalamic-pituitary-adrenal (HPA) axis that integrates stress and endocrine responses both in the brain and in peripheral tissues. CRHR1 is abundant in the endometrium and ovaries and has a role in developing endometriotic tissues, as demonstrated by the team's previous work. CRHR1 antagonists were introduced into clinical trials for mood and gastrointestinal disorders with little to no effect on those diseases and have never reached approval for commercial use. Previous work from the research team demonstrated that short-term treatment with antalarmin, a CRHR1 antagonist frequently used in pre-clinical experimentation, showed a 30% decrease in endometriosis development and a 60% decrease in the weight and size of endometriosis vesicles. In continuation of these efforts, the overarching goal is to develop and commercialize CRHR1 antagonists to treat endometriosis. The research team will focus on a compound recently out of patent and reached Phase 2 clinical trials but was not effective for depression, anxiety, or alcoholism. To begin addressing our goal, two specific aims were designed: on Aim 1, we will determine the effectiveness of a clinically relevant CRHR1 antagonist for endometriosis treatment, including its effectiveness in decreasing associated pain. Aim 2 will determine whether the CRHR1 antagonist affects the gonadal axis's cyclic hormonal activity, independent of antiproliferative activity. Both aims will be done using the well-established autotransplantation rat model of endometriosis, allowing for effective quantification and characterization of endometriotic vesicles. Completed aims will reveal the optimal intervention for halting endometriosis progression and predict possible mechanisms of action directly associated with the role of CRHR1 in the gonadal system. Future efforts will focus on how the CRHR1 antagonism impacts fertility and fecundity, which are critical factors to apply for re-introduction into clinical testing at the FDA. Bringing CRHR1 antagonists into the commercial field have the strong potential of decreasing surgical interventions in women with endometriosis, resulting in thousands of dollars saved in healthcare and indirect costs. The research team has identified the potential to repurpose CRHR1 antagonists, but before being re-introduced into clinical trials, additional proof of action and pre-clinical effectiveness is needed.