Repurposing CRH antagonists for the treatment of endometriosis

重新利用 CRH 拮抗剂治疗子宫内膜异位症

• 批准号: 10746682
• 负责人: Caroline B Appleyard
• 金额: $ 7.12万
• 依托单位: SUR180 THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10746682
• 关键词: Address; Affect; Aftercare; Alcoholism; Anxiety; Autologous Transplantation; Brain; Chronic; Clinical Trials; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Development; Disease; Effectiveness; Endocrine; Endometrium; Facilities and Administrative Costs; Fertility; Future; Gastrointestinal Diseases; Goals; Health Care Costs; Hormonal; Hormone Antagonists; Infertility; Intervention; Legal patent; Marketing; Masks; Mental Depression; Modeling; Mood Disorders; Operative Surgical Procedures; Ovary; Pain; Periodicity; Peripheral; Pharmacological Treatment; Phase II Clinical Trials; Quality of life; Rattus; Recurrence; Recurrent pain; Research; Role; Stress; System; Therapeutic; Tissues; Vesicle; Wages; Weight; Withholding Treatment; Woman; Work; aged; alternative treatment; antagonist; antalarmin; clinically relevant; commercialization; design; effectiveness evaluation; endometriosis; hypothalamic-pituitary-adrenal axis; novel; pain-related disability; pre-clinical; receptor; reproductive; research clinical testing; response

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.

项目摘要 子宫内膜异位症是一种慢性病，影响了全世界10％的生殖老年妇女。不幸的是，起来 59％的子宫内膜异位症女性对可用治疗没有反应，并继续遭受 治疗停止后，子宫内膜异位相关的疼痛或复发性疼痛。因此，治疗替代方案 迫切需要偏离目前的治疗重点。皮质营养素释放激素受体 类型1（CRHR1）是一个很大程度上未开发的目标。皮质激素释放激素（CRH），激活该激素 CRHR1是下丘脑 - 垂体 - 肾上腺（HPA）轴的关键分子，它整合了应力和 内分泌反应在大脑和周围组织中。 CRHR1在子宫内膜中丰富， 如该团队先前的工作所证明的那样，卵巢并在开发子宫内膜组织中发挥作用。 将CRHR1拮抗剂引入了情绪和胃肠道疾病的临床试验中 对这些疾病的影响，从未获得商业用途的批准。研究的先前工作 团队证明了用Antalarmin（CRHR1拮抗剂）经常用于临床前使用的Antalarmin的短期治疗 实验显示，子宫内膜异位症的发育降低了30％，体重减轻了60％ 子宫内膜异位囊泡的大小。在继续这些努力时，总体目标是发展和 将CRHR1拮抗剂商业化以治疗子宫内膜异位症。研究小组最近将重点放在一个化合物上 脱离专利并达到2期临床试验，但对于抑郁，焦虑或酗酒无效。到 开始解决我们的目标，设计了两个具体目标：在AIM 1上，我们将确定一个 用于子宫内膜异位症治疗的临床相关CRHR1拮抗剂，包括其在降低的有效性 相关的疼痛。 AIM 2将确定CRHR1拮抗剂是否影响性腺轴的循环激素 活性，与抗增生活性无关。这两个目标都将使用良好的 自身移植大鼠子宫内膜异位症模型，允许有效定量和表征 子宫内膜囊泡。完成的目标将揭示停止子宫内膜异位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作用机理。 未来的努力将集中于CRHR1拮抗作用如何影响生育能力和繁殖力，这是关键因素 在FDA上申请重新引入到临床测试中。将CRHR1拮抗剂带入商业领域 具有减少子宫内膜异位症女性手术干预措施的强大潜力 在医疗保健和间接成本中节省了数千美元。研究小组已经确定了 重新利用CRHR1拮抗剂，但在重新引入临床试验之前，其他行动证明和 需要临床前的效力。