Novel, Non-hormonal Therapeutic for Endometriosis

项目概要： 该项目的最终目标是开发第一个疾病修饰（“治疗”）和非激素 治疗子宫内膜异位症。子宫内膜异位症被认为是妇女健康中最被忽视的流行病， 影响了全球约10%的女性。它是造成不孕不育和残疾的主要原因， 所有种族的青少年和妇女。令人震惊的是，到目前为止，还没有治愈这种慢性和普遍的 需要6-10年才能确诊的疾病。目前，子宫内膜异位症的管理是通过激素 治疗、疼痛疗法或手术干预--这些都不能逆转疾病或解决根本原因-- 往往不够。激素药丸和GnRH拮抗剂（导致“医学绝经”）， 子宫内膜异位症患者可引起许多不良副作用。许多患有子宫内膜异位症的女性 切除后5年内会复发。子宫切除术建议妇女谁不 通过侵入性较小的方法缓解疼痛。NICHD开发了一种非激素 子宫内膜异位症的治疗是一个高度优先的目标，这与2021-2025年NIH范围内的战略相对应 计划和“大胆预测”推进一个非激素治疗子宫内膜异位症的临床试验。我们 小组打算通过这一阶段IIB SBIR应用实现这一“大胆的预测”。 我们的团队通过靶向子宫内膜异位症的下游成分， 一种已知有助于子宫内膜异位症发病机制、子宫内膜迁移和侵袭的途径。我们 成功地完成了我们的SBIR快速通道赠款的第一阶段和第二阶段的里程碑。引线 候选物被鉴定为具有治疗功效而没有可观察到的毒性。主要候选人特别是 并选择性地抑制该下游组分，并在细胞效力测定，凋亡测定， 血清稳定性、膜渗透性和阴道吸收无刺激性。在体内， 重要的是表明了伴随着增加的细胞凋亡，减少的细胞凋亡， 增殖，并减少下游靶基因，而不诱导毒性或改变发情周期。 因此，我们的主要候选人表现出巨大的潜力，作为子宫内膜异位症治疗，以消除病变。 其他分子在学术环境中使子宫内膜异位症进展倒退，但具有脱靶或上游作用。 这些途径靶点使它们成为不期望的治疗剂，因为诱导了不期望的副作用。 在IIB期，我们将确定电极导线治疗的最小有效剂量，优化 主要候选药物的制剂，并完成IND使能毒理学研究，以提交IND包 交给食品药品管理局通过这样做，我们将开发一种非激素治疗，是疾病修饰;因此， 由于子宫内膜异位症治疗的高度未满足的需求，成功完成我们的目标将使我们能够 向FDA提交IND许可申请并开始临床试验。成功完成本 该项目将为患有子宫内膜异位症的妇女提供消除这种疾病的治疗方案。

PROJECT SUMMARY: The ultimate goal of the project is to develop the first disease-modifying (“curative”) and non-hormonal therapeutic for endometriosis. Endometriosis is considered the greatest overlooked epidemic in women’s health, affecting approximately 10% of women worldwide. It is a major 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 that takes 6-10 years to be diagnosed. Currently, the management of endometriosis is through hormonal treatment, 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 endometriosis can induce many undesirable side effects. Many women who undergo endometriosis excision will have recurrence within 5 years of surgery. Hysterectomies are recommended for women who do not experience relief through less invasive methods. NICHD has made the development of a non-hormonal therapeutic for endometriosis a high priority goal, which corresponds with the 2021-2025 NIH-wide strategic plan and “bold prediction” of advancing one non-hormonal therapeutic for endometriosis to clinical trials. Our group intends to accomplish this “bold prediction” with this Phase IIB SBIR application. Our team developed a novel therapeutic option for endometriosis by targeting a downstream component of a pathway known to contribute to endometriosis pathogenesis, endometrial migration and invasion. We successfully accomplished our milestones from both Phase I and II of our SBIR Fast-Track Grant. A lead candidate was identified that has therapeutic efficacy with no observable toxicity. The lead candidate specifically and selectively inhibits this downstream component and shows success in cell potency assays, apoptosis assays, serum stability, membrane permeability, and vaginal absorption without irritation. In vivo, the lead candidate importantly demonstrates endometriotic lesion regression accompanied by increased apoptosis, decreased proliferation, and decreased downstream target genes without inducing toxicity or alterations in estrous cyclicity. Thus, our lead candidate exhibits great potential to act as an endometriosis therapeutic to eliminate lesions. Other molecules have regressed endometriosis progression in academic settings, but have off-target or upstream pathway targets that make them undesirable therapeutics as undesired side effects are induced. During Phase IIB, we will determine a minimal efficacious dose of the lead therapeutic, optimize formulations of the lead candidate, and finish IND-enabling toxicology studies for submission of an IND package to the FDA. By doing so, we will develop a non-hormonal therapeutic that is disease-modifying; consequently, due to the high unmet need for endometriosis therapeutics, successful completion of our aims will allow us to submit our application to the FDA for IND allowance and commence clinical trials. Successful completion of this project will give women suffering from endometriosis a curative solution to eliminating the disease.