Cryopreservation and Transplantation of Ovarian Cortical Tissue for Fertility Preservation

卵巢皮质组织的冷冻保存和移植以保存生育能力

基本信息

批准号：
9288194
负责人：
Mary B Zelinski
金额：
$ 62.72万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-06 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288194
关键词：
3-Dimensional Adolescent Adolescent and Young Adult Adult Adverse effects Age Antral Autologous Autologous Transplantation Benign Biological Preservation Biomedical Engineering Birth Blood Vessels Blood flow Bone Marrow Transplantation Breast Cancer Patient Cancer Survivor Child Clinic Clinical Complex Computer Simulation Controlled Study Cortex of ovary Cryopreservation Detection Development Diagnosis Disease Embryo Embryology Embryonic Development Encapsulated Endocrine Environment Exposure to FDA approved Female Fertility Fibrin Foundations Freezing Future Germ Cells Goals Health Heterotopic Transplantation Human In Vitro Individual Infertility Interruption Investigation Investigational Therapies Late Effects Macaca mulatta Malignant Neoplasms Menopause Methods Modeling Mothers Non-Malignant Oocytes Ovarian Ovarian Tissue Ovary Parents Patients Population Premature Menopause Premature Ovarian Failure Prior Therapy Production Protocols documentation Radiation Radiation therapy Regulation Reporting Reproducibility Research Personnel Risk Running Safety Site Source Stromal Cells Survival Rate Survivors System Techniques Technology Tissues Translations Transplantation Transplanted tissue Ultrasonography Woman cancer cell cancer invasiveness cancer therapy cell type chemotherapy child bearing childhood cancer survivor clinical practice clinical translation contrast enhanced cryobiology experience functional outcomes girls improved in vivo innovative technologies nonhuman primate novel novel strategies offspring ovarian failure ovary transplantation pre-clinical research preimplantation prepuberty public health relevance restoration scaffold sound steroid hormone tool treatment effect vascular bed young adult young woman

项目摘要

DESCRIPTION (provided by applicant): The long-range goals of this proposal are to develop robust and reproducible methods for ovarian tissue cryopreservation and transplantation as options for fertility preservation in survivors of cancer or other benign conditions wherein ovaria function is compromised. While 80% of young patients currently survive their cancers, devastating side effects of chemo- or radiotherapies leave female survivors facing infertility due to ovarian failure. Cryopreservation of ovarian tissue remains the only option for prepubertal, adolescent and young women with cancer as well as adult patients for whom immediate cancer therapy is required. But, human ovarian tissue cryopreservation is considered experimental and hampered by several factors. Embryology clinics in the U.S. favor embryo and oocyte vitrification over slow-rate freezing, but there is no uniform protocol for vitrification of ovaria tissue. Although 30 human births have been reported from slow-rate freezing and transplantation to orthotopic sites, only 4 could claim that the transplanted tissue was known to be the source of the oocytes. Most young survivors will not have a healthy ovarian vascular bed as a transplantation site following cancer therapies. Cryopreservation is also the only option for patients contraindicated for ovarian transplantation due to the risk of reintroducing malignant cells. While in vitro follicle culture is under development, most studies use follicles isolated frm non-cryopreserved tissues. We successfully devised a method for vitrification of rhesus monkey ovarian tissue in a closed system, and demonstrated post-thaw function in vivo and in vitro. When transplanted to heterotopic sites, vitrified tissue resumes ovarian function, and yields mature oocytes capable of preimplantation embryonic development. Secondary follicles isolated from vitrified tissue and encapsulated for 3-dimensional (3D) culture survive, grow to antral stages and produce steroid hormones in vitro, but oocyte quality is poor. Since the ovarian cortex is composed of complex cell types that complicate cryopreservation, vitrification of individual follicles and subsequent 3D culture is a novel approach toward preserving gametes for young patients with highly invasive cancers. An elite panel of co-investigators and collaborators that bring expertise in both state-of-the-art cryobiology as well as pre-eminent experience in clinical ovarian transplantation will help us advance the current technology for more rapid translation to clinical practice for patients. Using the rhesus monkey, we propose to identify the transplantation site for optimal fertile function of both prepubertal and young adult ovarian cortical tissue, improve long-term transplant function via local administration of factors important for revascularization as well as follicular survival, and optimize vitrification of isolaed preantral follicles and their ability to yield competent oocytes following 3D culture in vitro. Liv births in nonhuman primates after these controlled studies will establish the safety and feasibilit of experimental therapies prior to clinical translation so girls and young women can be offered the best chances of becoming mothers after surviving cancer.

描述（由应用提供）：该提案的远程目标是为卵巢组织冷冻保存和移植提供可靠和可再现的方法，作为癌症生存或其他良性疾病的生育能力的选择，其中卵巢功能受到损害。虽然目前有80％的年轻患者在癌症中生存，但化学疗法或放射性疗法的毁灭性副作用使雌性生存因卵巢衰竭而面临不育症。卵巢组织的冷冻保存仍然是癌症前，青少年和年轻女性以及需要立即进行癌症治疗的成年患者的唯一选择。但是，人类卵巢组织冷冻保存被认为是实验性的，并受到了几个因素的阻碍。在慢速冻结方面，胚胎和卵母细胞玻璃化，但没有均匀的卵巢组织玻璃体方案。尽管已经据报道了30个人类生日，从慢速冻结和移植到原位部位，但只有4个可以声称移植的组织已知是卵母细胞的来源。癌症治疗后，大多数年轻的生存将不会成为健康的卵巢血管床作为移植部位。冷冻保存也是由于重新引入恶性细胞的风险而禁用卵巢移植的患者的唯一选择。尽管正在开发体外叶片培养，但大多数研究使用焦点是分离的FRM非晶体组织。我们成功地设计了一种在封闭系统中玻璃猴卵巢组织玻璃化的方法，并在体内和体外表现出了透后的功能。当移植到异位部位时，玻璃组织会恢复卵巢功能，并产生能够植入前胚胎发育的成熟卵母细胞。从玻璃体组织中分离出来的二维（3D）培养物存活，生长到肛门阶段并在体外产生立体恐怖剂，但卵母细胞质量很差。由于卵巢皮质由复杂的冷冻保存复杂的复杂细胞类型组成，因此对个体焦点的玻璃化和随后的3D培养是一种新型的方法，可以为具有高度侵入性癌症的年轻患者保存游戏。由共同投资者和合作者组成的精英小组，在最先进的冷冻生物学以及临床卵巢移植方面的杰出经验中为我们提供了专业知识，这将有助于我们促进当前的技术，以更快地将患者的临床实践转化为临床实践。使用恒河猴，我们建议鉴定移植位点，以最佳的肥沃功能，以培育卵巢皮质组织的最佳肥沃功能，通过局部施用对血运重建和卵泡存活重要的因素来改善长期移植功能，并优化孤立的preantral fleantral follatral follatral follatal follal follal follicles和它们的能力，以产生能力和效率的能力，以造成纯正的效果依赖于3次培养型ocytron。在这些对照研究之后，非人类初级的LIV出生将在临床翻译之前确定实验疗法的安全性和可行性，因此可以为女孩和年轻女性提供最佳的机会，成为癌症生存后成为母亲的最佳机会。