Novel, Non-hormonal Therapeutic for Endometriosis

子宫内膜异位症的新型非激素疗法

基本信息

批准号：
10238133
负责人：
Katherine Anne Burns
金额：
$ 111.6万
依托单位：
ENDOMET BIOSCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238133
关键词：
Address Affect Affinity Animal Model Animal Testing Area Biodistribution Biological Assay Bone Regeneration Boston Cell Line Cell Membrane Permeability Cell Nucleus Cell model Cells Chronic Clinical Clinical Trials Critical Pathways Crystallization Cytoplasm Diagnosis Disease Disease Progression Dose Endometrial Ensure Epidemic Ethnic Origin Excision Exhibits Female Funding Future Gene Expression Gene Proteins Goals Gonadotropin Releasing Hormone Inhibitor Head Hormonal Hormones Human Hysterectomy Immunohistochemistry Industry Infertility Investigation Lead Lesion Libraries Link Medical Membrane Menopause Methods Modeling Modification Mus National Institute of Child Health and Human Development Operative Surgical Procedures Pain management Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Phase Phase I Clinical Trials Plant Roots Preparation Property Proteins Protocols documentation RNA Rattus Records Reporter Research Research Priority Safety Serum Specificity Surface Plasmon Resonance Testing Therapeutic Tissues Toxic effect Treatment Efficacy Vagina Vaginal Ring Western Blotting Woman Women&apos s Health Work beta catenin disability endometriosis experience experimental study improved in vitro Assay in vivo inhibitor/antagonist lead candidate lead optimization member migration mouse model novel novel therapeutics peptide structure peptidomimetics pharmacokinetics and pharmacodynamics pill pre-clinical preclinical development prevent programs protein biomarkers side effect small molecule success therapeutic candidate transcription factor uptake young woman

项目摘要

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.

该项目的目的是开发首个用于子宫内膜异位症的疾病改良，非激素治疗（EMS）被认为是妇女健康中最大的流行病妇女在全球范围内。迄今为止，所有种族都令人震惊。 EMS诊断为6至10岁的美国妇女普通女性，当前的荷尔蒙，疼痛管理方案疗法或手术干预措施（无法扭转疾病或解决根本原因）通常是荷尔蒙药丸和GNRH拮抗剂 EMS可以诱导许多可安线的副作用。在手术后的5年内，建议没有救济的女性我们的团队较少的侵入性方法通过针对下游开发了一种新颖的治疗选择已知有助于子宫内膜异位发病机理和子宫内膜迁移和子宫内膜迁移和 Invision。效力和繁殖分析，记者测定，血清稳定性，膜渗透性，毒性鼠标研究，并表现出充当子宫内膜异位症治疗的巨大潜力。途径在学术环境中的EMS进展逆转，但具有脱离目标或上游途径目标在这个新型项目中诱发了不希望的副作用，我们将确定最有前途的2个大环肽，以抑制EMS细胞的迁移。 pk/ pk/ pd，靶向效果，确认缺乏靶向效果，侵害和质量的侵袭和迁移，以及我们在波士顿中心的合作者使用初级EMS细胞D的功效子宫内膜异位症已从不同的患者中切除带有临床记录的标准方案。还将评估肽的子宫内膜异位症体内动物模型，并将确认靶向效应通过RNA的QPCR，免疫组织化学和蛋白质印迹分析。可以在铅候选肽上进行，以获得更多不介于肽的（小分子）药物一旦经过验证和优化，这些综合剂将会发挥作用。在第二阶段进行临床前研究和毒性研究。随后的IIB IIB阶段IIB申请为亲自审议准备的资金申请 FDA在为IND准备1阶段临床试验时。