Novel, Non-hormonal Therapeutic for Endometriosis

该项目的目标是开发第一个疾病修饰，非激素治疗子宫内膜异位症 （EMS）。EMS被认为是妇女健康中最大的被忽视的流行病， 全世界的女人。它是全球青少年和妇女不孕不育和残疾的头号原因。 所有种族。令人震惊的是，到目前为止，还没有治愈这种慢性和流行疾病的方法。因为它需要一个 平均美国妇女6-10年被诊断为EMS，目前的管理协议的激素，疼痛， 治疗或手术干预-无法逆转疾病或解决根本原因-通常 不足激素药丸和GnRH拮抗剂（导致“医学绝经”）处方给患者 EMS会引起许多不良的副作用。许多妇女谁接受EMS切除将有复发 手术后5年内。子宫切除术建议妇女谁不经历救济通过 更少的侵入性方法。我们的团队已经开发了一种新的治疗选择EMS的目标是下游 已知有助于子宫内膜异位症发病机制和子宫内膜迁移的途径组分， 入侵我们的大环肽组特异性抑制这种下游组分，并在细胞中显示出成功 效价和增殖试验、报告基因试验、血清稳定性、膜渗透性、小鼠毒性 研究，并表现出巨大的潜力，作为子宫内膜异位症的治疗。其他分子靶向 通路在学术环境中逆转了EMS进展，但有脱靶或上游通路靶点 从而引起不希望的副作用。在这个新的项目中，我们将确定最有前途的2大环肽，抑制EMS细胞的迁移和侵袭，并确认其在EMS动物模型中的疗效。将使用我们在波士顿癌症研究中心的合作者捐赠的原代EMS细胞评估化合物的细胞效力、PK/PD、靶向效应、确认缺乏脱靶效应、抑制细胞侵袭和迁移以及功效。 子宫内膜异位症。从不同患者中切除细胞，并根据EPHECT收集 标准方案和随附的临床记录。我们的大环化合物的PK、疗效和生物分布 还将在子宫内膜异位症的体内动物模型中评估肽，并将证实靶向效应 通过RNA的qPCR、免疫组织化学和蛋白质印迹分析。药物化学优化将 对先导候选肽进行，以获得最佳的临床药物谱， 非天然的拟肽（小分子样）试剂。一旦经过验证和优化，这些化合物将 进入II期临床前研究和毒性研究。这些实验将为我们准备一个 随后的IIB期申请，以资助IND毒性实验，为与 FDA，因为我们正在为IND的1期临床试验做准备。

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.