Optimized protocols for ovarian tissue cryopreservation and novel modRNA-based approaches to improve transplantation outcomes for fertility preservation in chronically diseased girls

卵巢组织冷冻保存的优化方案和基于 modRNA 的新型方法可改善慢性病女孩生育力保存的移植结果

• 批准号: 10458028
• 负责人: Daylon J James
• 金额: $ 25.93万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-29 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458028
• 关键词: Acute; Address; Adolescent; Adult; Adverse effects; Affect; Animal Model; Attention; Autologous Transplantation; Cancer Patient; Child; Childhood; Chronic; Chronic Disease; Clinical; Cryopreservation; Development; Diagnosis; Disease; Disease remission; Embryo; Endocrine; Environment; FDA approved; Female; Fertility; Formulation; Foundations; Freezing; Germ Cells; Goals; Gonadal structure; Graft Survival; Health; Human; Infertility; Inflammatory; Live Birth; Longevity; Macaca; Macaca mulatta; Malignant Neoplasms; Messenger RNA; Methodology; Methods; Modality; Molecular; Oocytes; Organ Donor; Outcome; Output; Ovarian; Ovarian Follicle; Ovarian Tissue; Ovarian tissue cryopreservation; Ovariectomy; Pathology; Patient Representative; Patients; Phase; Premature Menopause; Primordial Follicle; Procedures; Production; Productivity; Protocols documentation; Quality of life; Recombinants; Recovery; Rhesus; Site; Slice; Standardization; Survival Rate; System; Testing; Therapeutic; Thinness; Tissue Survival; Tissue Transplantation; Tissues; Transplantation; VEGFA gene; Work; Xenograft procedure; base; chemotherapy; experimental study; fertility preservation; girls; human tissue; improved; mullerian-inhibiting hormone; novel; ovarian reserve; ovary transplantation; patient population; personalized diagnostics; post-transplant; pre-clinical; prepuberty; preservation; reproductive; success; young adult

Project Summary With increased diagnostic precision and expanded treatment options, the health and lifespan of children born with chronic diseases has extended significantly into adulthood, drawing attention to preserving their quality of life and reproductive options. Unfortunately, the pathology of many chronic conditions can have negative consequences for the gonad, resulting in infertility and/or premature menopause. Cryopreservation (and later auto-transplantation) of whole ovarian tissue could provide a means of “safe- guarding” ovarian reserve from the gonadotoxic effects of disease pathology, and this approach has been utilized in cancer patients to yield at least 100 live births since early attempts more than a decade ago. Although this approach is effective, the viability and productivity of cryopreserved ovarian tissue is drastically undermined by the inflammatory, ischemic environment within the graft during the acute phase post-transplant. This proposal leverages the potent bioactivity and straightforward delivery of modified mRNA (modRNA) as a therapeutic approach to improving the viability and output of ovarian tissue autografts. Using a xenograft platform developed by our group, we will investigate the potential for modRNA to: 1) improve viability and output of ovarian tissue transplanted for the purpose of fertility preservation; 2) maintain a robust pool of ovarian follicles in a quiescent primordial state that will serve as a long-term reservoir for normalization of endocrine function and oocyte output; and 3) demonstrate the efficacy of this approach in a highly relevant pre-clinical animal model, rhesus macaque. With these experiments we will establish a foundation for robust, repeatable and FDA-approvable methods for ovarian tissue cryopreservation/auto-transplantation in chronically diseased girls that wish to maintain their reproductive options.

项目摘要 随着诊断精度和扩大治疗方案的提高，儿童的健康和寿命 出生于慢性疾病已经大大扩展到成年，引起人们的注意 生活质量和生殖选择。不幸的是，许多慢性病的病理可能会有 性腺的负面后果，导致不育症和/或更年期。 整个卵巢组织的冷冻保存（后来的自动转移）可以提供“安全” 保护“卵巢储备免受疾病病理的性腺毒性作用，这种方法一直是 自十多年前早期尝试以来，在癌症患者中使用至少100个活产。 尽管这种方法是有效的，但是冷冻保存卵巢组织的生存能力和生产力是 急性期在移植物内部炎症性的缺血环境大为破坏 移植后。 该提案利用了修改的mRNA的潜在生物活性和直接递送 （ModRNA）作为改善卵巢组织自体移植的生存能力和输出的治疗方法。 使用我们小组开发的异种移植平台，我们将研究ModRNA的潜力：1） 改善移植的卵巢组织的活力和输出，以保存生育； 2） 将坚固的卵巢卵泡池保持在静止的原始状态，该状态将作为长期 用于内分泌功能和卵母细胞输出的归一化库； 3）证明这一点的效率 在高度相关的临床前动物模型恒河猴中的方法。通过这些实验，我们将 为卵巢组织的可靠，可重复和FDA批准的方法建立基础 渴望维持其生殖的长期宣告的女孩的冷冻保存/自动转移 选项。

项目成果

Exogenous insulin-like growth factor 1 accelerates growth and maturation of follicles in human cortical xenografts and increases ovarian output in mice.

• DOI: 10.1016/j.xfss.2021.07.002
• 发表时间: 2021-08
• 期刊: F&S science
• 作者: Man, Limor;Lustgarten Guahmich, Nicole;Kallinos, Eleni;Park, Laura;Caiazza, Barbara;Khan, Monica;Liu, Zong-Ying;Patel, Ritaben;Torres, Carmen;Lekovich, Jovana;Zhong, Liangwen;Bodine, Richard;Wen, Duancheng;Zaninovic, Nikica;Schattman, Glenn;Rosenwaks, Zev;James, Daylon
• 通讯作者: James, Daylon

Xenograft model of heterotopic transplantation of human ovarian cortical tissue and its clinical relevance.

• DOI: 10.1530/rep-22-0114
• 发表时间: 2023-01-01
• 期刊: REPRODUCTION
• 影响因子: 3.8
• 作者: Man, Limor;Lustgarten Guahmich, Nicole;Kallinos, Eleni;Park, Laura;Bodine, Richard;Zaninovic, Nikica;Schattman, Glenn;Rosenwaks, Zev;James, Daylon
• 通讯作者: James, Daylon