Novel, Non-hormonal Therapeutic for Endometriosis

该项目的目标是开发第一种治疗子宫内膜异位症的非激素疗法。 (EMS)。EMS被认为是妇女健康中最被忽视的流行病，影响到大约10%的 世界各地的女性。它是全世界青少年和妇女不孕和残疾的头号原因。 所有种族。令人震惊的是，到目前为止，这种慢性和流行的疾病还没有治愈方法。因为这需要一个 美国女性平均6-10年被诊断为EMS，目前的治疗方案是荷尔蒙、疼痛 治疗或外科干预--未能扭转疾病或解决根本原因--通常是 还不够。激素药片和促性腺激素释放激素拮抗剂(导致“内科绝经”)处方给患有 EMS会引起许多不良副作用。许多接受子宫内膜异位症切除的女性会复发 在手术后5年内。对于没有通过子宫切除获得缓解的妇女，建议进行子宫切除术 侵入性较小的方法。我们的团队已经开发出一种治疗EMS的新方法，它针对的是下游的 已知的有助于子宫内膜异位症发病和子宫内膜移行的途径的组成部分 入侵。我们的大环肽小组专门抑制了这个下游成分，并在细胞中显示了成功 效力和增殖试验、报告试验、血清稳定性、膜通透性、小鼠毒性 研究，并显示出巨大的潜力，作为子宫内膜异位症的治疗。其他靶向于 途径在学术环境中逆转了EMS进展，但具有非靶点或上游途径靶点 会引起不良的副作用。在这个新的项目中，我们将确定最有希望的两个大环肽，它们可以抑制EMS细胞的迁移和侵袭，并在EMS动物模型中证实其有效性。这些化合物将使用我们在波士顿中心的合作者捐赠的原代EMS细胞进行细胞效力、PK/PD、靶向效应、确认缺乏靶向效应、抑制细胞侵袭和迁移以及有效性的评估。 子宫内膜异位症。这些细胞是从不同的患者身上提取出来的，并根据EPHECT进行了收集 附有临床记录的标准方案。我们的大环化合物的PK、有效性和生物分布 多肽还将在子宫内膜异位症的体内动物模型中进行评估，并将证实其靶向效应。 通过定量聚合酶链式反应、免疫组织化学和蛋白质印迹分析。药物化学优化将 对主要候选肽执行，以通过变得更多 非天然的、模拟多肽(小分子)的制剂。一旦经过验证和优化，这些化合物将 进入第二阶段的临床前研究和毒性研究。这些实验将为我们 随后的第IIB阶段申请资助IND毒性试验，为与 FDA正在为第一阶段临床试验的IND做准备。

The goal of the project is to develop the first disease-modifying, non-hormonal therapeutic for endometriosis (EMS). EMS is considered the greatest overlooked epidemic in women's health, affecting approximately 10% of women worldwide. It is the number one cause of infertility and disability among adolescents and women across all ethnicities. Shockingly, to date, there is no cure for this chronic and prevalent disease. Because it takes an average US woman 6–10 years to be diagnosed with EMS, the current management protocols of hormonal, pain therapies, or surgical interventions—which fail to reverse the disease or address the root cause—are often insufficient. Hormone pills and GnRH antagonists (causing “medical menopause”) prescribed to patients with EMS can induce many undesirable side effects. Many women who undergo EMS excision will have reoccurrence within 5 years of surgery. Hysterectomies are recommended for women who do not experience relief through less invasive methods. Our team has developed a novel therapeutic option for EMS by targeting a downstream component of a pathway known to contribute to endometriosis pathogenesis and endometrial migration and invasion. Our panel of macrocyclic peptides specifically inhibits this downstream component and shows success in cell potency and proliferation assays, reporter assays, serum stability, membrane permeability, toxicity mouse studies, and exhibits great potential to act as an endometriosis therapeutic. Other molecules targeting the pathway have reversed EMS progression in academic settings, but have off-target or upstream pathway targets that induce undesired side effects. In this novel project, we will identify the most promising 2 macrocyclic peptides that inhibit the migration and invasion in EMS cells and confirm its efficacy in an EMS animal model. The compounds will be evaluated for cellular potency, PK/PD, on-target effects, confirm lack of off-target effects, inhibition of cellular invasion and migration, and efficacy using primary EMS cells donated by our collaborators at the Boston Center for Endometriosis. The cells have been excised from different patients and collected in accordance to the EPHECT standard protocols with accompanying clinical records. The PK, efficacy, and biodistribution of our macrocyclic peptides will also be evaluated an in vivo animal models of endometriosis, and on-target effects will be confirmed through qPCR of RNA, immunohistochemistry, and western blot analysis. Medicinal chemistry optimization will be performed on the lead candidate peptides to obtain an optimal clinical drug profile by becoming more unnatural, peptidomimetic (small molecule-like) agents. Once validated and optimized, these compounds will enter into preclinical investigation and toxicity studies in Phase II. These experiments will prepare us for a subsequent Phase IIB application to fund IND toxicity experiments in preparation for pre-discussions with the FDA as we prepare for an IND for Phase 1 clinical trials.