Ex vivo whole ovary culture system for screening gonadotoxicity during drug development

用于在药物开发过程中筛选性腺毒性的离体全卵巢培养系统

基本信息

批准号：
10823136
负责人：
Alison Y Ting
金额：
$ 30.93万
依托单位：
EXPANSE BIO LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10823136
关键词：
3-Dimensional Age Animals Apoptosis Back Basic Science Biological Assay Blood Vessels Bone Diseases Cancer Patient Carbon Dioxide Cardiovascular Diseases Cattle Cells Cessation of life Clinical Research Cognition Disorders Collaborations Collection Computer software Culture Media Cyclophosphamide Cytotoxic agent Development Devices Diagnosis Drug Screening Drug usage Endocrine Ethics Evaluation Exposure to Family suidae Feedback Female Fertility Future Gene Expression Profiling Genetic Transcription Growing Follicle Health Histology Hour Human Immunohistochemistry In Vitro Incubators Industrialization Infertility Lactic acid Laminin Malignant Childhood Neoplasm Malignant Neoplasms Mammals Measurement Menopause Metabolic Microfluidics Modeling Molecular Morphology Nutrient Oncologist Oocytes Organ Ovarian Ovarian Follicle Ovary PECAM1 gene Patients Perfusion Pharmaceutical Preparations Phase Premature Menopause Premature Ovarian Failure Premenopause Protocols documentation Quality of life Risk Rodent Rodent Model Sheep Small Business Innovation Research Grant Structure Survival Rate System Technology Testing Therapeutic Therapeutic Agents Tissue Banks Tissues Toxic effect Transplantation Woman autocrine blood damage cancer diagnosis cancer therapy cell type chemotherapeutic agent chemotherapy commercialization cost effective cytotoxic design dosage drug candidate drug development experience folliculogenesis girls human model improved in vivo meter novel novel therapeutics ovarian damage ovotoxicity paracrine phase 2 study porcine model pressure protein expression screening side effect steroid hormone three dimensional cell culture timeline tissue/cell culture treatment planning wasting young cancer survivor young woman

项目摘要

ABSTRACT Background: In the U.S., over 200,000 girls and women age 0-49 are diagnosed with cancer annually. While improved diagnosis and treatment have led to increased survival rates (75% in premenopausal and 85% in childhood cancer patients), devastating side effects of cancer therapies include premature ovarian failure, infertility and menopause-related health risks. The current industrial standard for detecting and de-risking ovotoxicity is to use in vivo rodent models or 2D/3D in vitro ovarian cells/tissue culture with significant drawbacks. This Phase I proposal aims to develop an ex vivo system for long-term assessment of ovarian damage at morphological, functional, and molecular levels, in a whole ovary model. Approach: The objectives for this Phase I SBIR proposal are to 1) build a novel ex vivo microfluidic organ perfusion device that will support culture of whole ovaries for 7 days and establish optimal culture conditions, as well as to 2) test this culture system using a chemotherapy medication, 4-hydroperoxy cyclophosphamide, a metabolite from one of the most commonly used drugs, cyclophosphamide. Endpoints will include the ability of oocytes to mature in vitro, as well as protein and RNA expression of markers that demonstrate follicular health and apoptosis. The resultant technology of this project will be the first perfusion unit designed for the whole ovary of large mammals (including humans) and can control perfusion pressure, flow rate and treatment concentration with a build-in feedback mechanism to maintain constant pressure during perfusion. Future Directions and Commercialization potential: This phase I project will provide crucial proof-of-principle for future Phase II studies to test the ability of the whole ovary culture system for longer culture period (1 month), collaborate with drug companies to screen drug candidates for their ovotoxicity or ovoprotection potentials, and to examine long-term endocrine and fertility consequences by transplanting chemotherapeutics-treated ovaries back to the host animal. The technology to maintain prolonged live/functional has the added potential for observing follicle maturation and its related studies (basic and clinical research). Successful development of an ex vivo whole ovary culture system will set new industrial standards during drug development because it will allow the use of ovaries from larger mammals (including women) without causing harm and death to the animal, and it will allow evaluation of the whole ovary while mimicking in vivo delivery of toxic chemotherapeutics.

抽象的背景：在美国，每年被诊断出200,000多名0-49岁的女孩和妇女。尽管改善诊断和治疗导致了生存率提高（绝经前75％，85％儿童癌症患者），癌症疗法的毁灭性副作用包括过早的卵巢衰竭，不育和更年期相关的健康风险。当前用于检测和脱离风险的工业标准卵毒性是在体内啮齿动物模型中使用具有显着缺陷的体外卵巢细胞/组织培养的2D/3D。该阶段I建议旨在开发一个离体系统，以长期评估卵巢损伤在整个卵巢模型中，形态学，功能和分子水平。方法：I阶段I SBIR提案的目标是1）建立一个新颖的离体微流体器官灌注装置将支持整个卵巢培养7天并建立最佳培养条件，例如以及2）使用化学疗法药物，4-氢氧基环磷酰胺，A测试该培养系统来自最常用的药物之一，环磷酰胺的代谢产物。终点将包括在体外成熟的卵母细胞，以及蛋白质和标记的RNA表达，这些标志物证明了卵泡健康和凋亡。该项目的最终技术将是为整个设计的第一个灌注单元大型哺乳动物（包括人）的卵巢，可以控制灌注压力，流速和治疗具有建筑反馈机制的浓度，以在灌注过程中保持恒定压力。未来的方向和商业化潜力：该阶段I项目将提供至关重要的原理证明对于未来的II期研究，可以测试整个卵巢培养系统在更长的培养期（1个月）中的能力，与制药公司合作，以筛选候选药物的产卵毒性或产卵潜力，以及通过移植化学疗法治疗的卵巢来检查长期内分泌和生育能力回到宿主动物。维持长时间的活/功能的技术具有额外的潜力观察卵泡成熟及其相关研究（基础和临床研究）。成功发展体内整个卵巢培养系统将在药物开发期间树立新的工业标准，因为它将允许使用较大哺乳动物（包括妇女）的卵巢，而不会造成动物伤害和死亡，它将允许对整个卵巢进行评估，同时模仿有毒化学治疗药的体内递送。