Novel, Non-hormonal Therapeutic for Endometriosis

子宫内膜异位症的新型非激素疗法

• 批准号: 10551782
• 负责人: Katherine Anne Burns
• 金额: $ 105万
• 依托单位: ENDOMET BIOSCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551782
• 关键词: Address; Affect; Animals; Apoptosis; Area; Binding; Binding Proteins; Biological Assay; Biological Sciences; Body Weight; Canis familiaris; Cardiac; Cell Membrane Permeability; Cell Nucleus; Cells; Chronic; Cicatrix; Clinical; Clinical Chemistry; Clinical Trials; Corn Oil; Cyclic Peptides; Data; Data Reporting; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Kinetics; Electrodes; Endometrial; Epidemic; Estrus; Ethnic Origin; Excision; Exhibits; Female; Filler; Formulation; Future; Generations; Genes; Genetic Transcription; Goals; Gonadotropin Releasing Hormone Inhibitor; Grant; Growth; Half-Life; Heart; Hematology; Hormonal; Hormones; Human; Hysterectomy; In Vitro; Infertility; Ion Channel; Lead; Lesion; Libraries; Medical; Membrane; Menopause; Methods; Modeling; Monkeys; Mus; National Institute of Child Health and Human Development; Normal tissue morphology; Operative Surgical Procedures; Oral; Ovary; Pain; Pain management; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Periodicity; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology Study; Phase; Phase I Clinical Trials; Plant Roots; Plasma; Pluripotent Stem Cells; Preparation; Production; Proteins; Protocols documentation; Rattus; Recurrence; Regulation; Research; Research Priority; Risk; Safety; Serum; Small Business Innovation Research Grant; Strategic Planning; System; Testing; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; United States National Institutes of Health; Uterus; Vagina; Vaginal delivery procedure; Ventricular Arrhythmia; Woman; Women' s Health; absorption; appropriate dose; beta catenin; day length; disability; electrical property; endometriosis; first-in-human; healthy volunteer; in vivo; inhibitor; irritation; lead candidate; logarithm; migration; mouse model; neurobehavioral; novel; novel therapeutics; patch clamp; patient population; peptide drug; pill; pre-clinical; preclinical study; reproductive; side effect; success; transcription factor; treatment duration; young woman

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.

项目摘要： 该项目的最终目标是开发第一个疾病改良（“治愈”）和非激素 子宫内膜异位症的治疗性。 在全球范围内，大约有10％的妇女。 迄今为止，所有种族的青少年和妇女都无法治愈 目前需要诊断为6 - 10年的疾病。 治疗，疼痛疗法或手术干预措施 - 无法扭转疾病或解决根本原因} 通常不足。 子宫内膜异位症的患者会诱导许多可安线的副作用。 在5个Youars手术中，将其重复出现。 通过减少侵入性方法体验缓解。 子宫内膜异位症的治疗性高优先级目标，与2021-2025 NIH范围的战略相对应 计划和“大胆的预测”将一种非激素治疗性用于子宫内膜异位症 小组打算使用此阶段IIB SBIR应用程序来完成此“大胆预测”。 我们的团队通过针对一个新型的子宫内膜异位症治疗选择。 已知有助于子宫内膜异位发病机理，子宫内膜迁移和入侵的途径 成功的sbir Sbir Sbir Sbir Sbir Sbirack Sbirack Grant从I和II中实现了我们的里程碑 候选人被鉴定出可识别的效力。 并有选择地抑制这种下游成分和细胞效力测定中的成功，凋亡分析， 血清稳定性，膜渗透性和阴道吸收，而无需刺激性。 重要的是表明子宫内膜损伤调节伴随着凋亡增加，减少 延伸性和下游靶基因降低，而无需诱导毒性或发情循环的改变。 因此，我们的主要候选人表现出充当子宫内膜异位症治疗的巨大潜力，可消除病变。 其他分子在学术环境中已回归子宫内膜异位症的进展，但具有靶向或上游 诱发了不希望的副作用的途径靶标，使其成为不希望的治疗剂。 在IIB期间，我们将确定铅治疗的最小有效剂量剂量，优化 主要候选者的表述，并完成提交IND软件包的毒理学研究 到FDA。 由于对子宫内膜异位症治疗的高度需求，成功压缩我们的目标将使我们能够 将我们的申请提交给FDA进行夸张和评论临床试验。 项目将使患有子宫内膜异位症的妇女成为消除疾病的治疗方法。