Immuno-Isolating capsule for delivery of cell-based therapy for restoration of ovarian endocrine function in an animal model

免疫隔离胶囊用于在动物模型中提供基于细胞的治疗以恢复卵巢内分泌功能

• 批准号: 10677892
• 负责人: Ariella Shikanov
• 金额: $ 66.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677892
• 关键词: Acceleration; Adolescent; Adult; Allogenic; Allografting; Animal Model; Animals; Autologous; Autologous Transplantation; Bone Marrow Transplantation; Cancer Survivor; Cardiovascular Diseases; Cell Therapy; Chemotherapy and/or radiation; Child; Circulation; Competence; Complication; Cryopreservation; Data; Development; Diabetes Mellitus; Diffusion; Disease remission; Embryonic Development; Encapsulated; Endocrine; Engineering; Estrogen deficiency; Estrogens; Estrus; Event; Exposure to; Face; Female; Female Adolescents; Fertility; Fertilization; Follicle Stimulating Hormone; Goals; Growth; Health; Height; Hematologic Neoplasms; Hormonal; Hormone imbalance; Hormone replacement therapy; Hormones; Human; Hydrogels; Immune; Immune response; Immunity; Immunosuppression; Impairment; Implant; Intervention; Life; Longevity; Malignant Childhood Neoplasm; Metabolic; Modernization; Mus; Muscular Atrophy; Nature; Obesity; Oocytes; Osteopenia; Outcome; Ovarian; Ovarian Tissue; Ovarian hormone; Ovary; Patients; Pattern; Periodicity; Physiological; Pilot Projects; Preclinical Testing; Primates; Progesterone; Puberty; Recurrent Malignant Neoplasm; Research; Risk; Rodent; Sterility; Stimulus; Survival Rate; Testing; Tissues; Transplantation; Treatment-related toxicity; United States; anticancer treatment; bone quality; cancer cell; cancer recurrence; cancer risk; cancer therapy; capsule; chemotherapy; clinical translation; clinically relevant; cognitive development; cytotoxic; design; efficacy testing; ethylene glycol; folliculogenesis; girls; graft function; implantation; improved; isoimmunity; loss of function; malignant breast neoplasm; meter; millimeter; mouse model; negative affect; nonhuman primate; novel; oocyte quality; ovary transplantation; premature; prepuberty; prevent; primary ovarian insufficiency; response; restoration; risk minimization; standard of care; thrombotic; tool; translation to humans; translational potential; young woman

Premature ovarian insufficiency (POI) is a common complication of anticancer treatments, such as chemotherapy and bone marrow transplantation, due to treatment toxicity. In female cancer survivors POI causes sterility, and loss of the ovarian endocrine function, which in turn results in premature osteopenia, muscle wasting, and accelerated cardiovascular disease. These long-lasting effects are significant, particularly for young girls reaching puberty. Our results in an ovariectomized adult mouse model have demonstrated that transplantation of an ovarian allograft encapsulated in an immunoisolating hydrogel-based capsule restores normal physiological endocrine ovarian function without eliciting immune rejection. Yet, rodents present limitations for clinical translation to humans, such as 1) the small size of a prepubertal female limits intervention before puberty and onset of puberty is regulated differently in primates than in rodents; 2) the small size and multiovulatory character of the mouse ovaries have a limited translational potential; and 3) the differences in immune response limit the reach of our findings. To overcome these challenges and increase the translational potential, we propose to extend preclinical testing of our therapy into non-human primates (NHPs). We will test the efficacy of encapsulated ovarian allograft to initiate physiological puberty in adolescent NHPs, we will study the longevity of graft function as well as the dynamics of the recipient’s immune response to initial and repeat implantations and evaluate the quality of oocytes grown in capsules for fertility restoration. If successful, this approach will offer a clinically relevant and unexplored tool to restore ovarian endocrine function in young women with POI. We have demonstrated in an ovariectomized adult mouse model that implantation of an ovarian allograft encapsulated in an immunoisolating hydrogel-based capsule restores normal physiological endocrine ovarian function without eliciting immune rejection. Yet, rodents present limitations for clinical translation to humans, such as the small size of a prepubertal female, which limits intervention before puberty and the differences in allo-immune response between rodents and humans. The proposed research To overcome these challenges and increase the translational potential, we propose to extend preclinical testing of our therapy into non-human primates (NHPs). We will test the efficacy of encapsulated ovarian allograft to initiate physiological puberty in adolescent NHPs, we will study the longevity of graft function as well as the dynamics of the recipient’s immune response to initial and repeat implantations and evaluate the quality of oocytes grown in capsules for fertility restoration. If successful, this approach will offer a clinically relevant and unexplored tool to restore ovarian endocrine function in young women with POI.

卵巢功能不全(POI)是抗癌治疗的常见并发症，如 化疗和骨髓移植，因治疗毒副反应。女性癌症幸存者 POI导致不孕不育和卵巢内分泌功能丧失，进而导致早产 骨量减少，肌肉萎缩，加速心血管疾病。这些长期的影响是 意义重大，特别是对进入青春期的年轻女孩来说。我们在去卵巢的成年小鼠身上的结果 模型表明，移植的卵巢被包裹在一个 免疫隔离水凝胶胶囊恢复正常卵巢生理内分泌功能 而不会引起免疫排斥。然而，啮齿动物在临床移植到人类方面存在局限性， 例如1)青春期前女性的小身材限制了青春期之前和青春期开始之前的干预 在灵长类动物中的调节不同于啮齿类动物；2)小的体积和多排卵的特征 小鼠卵巢的翻译潜力有限；3)免疫反应的差异限制了 我们调查结果的覆盖范围。为了克服这些挑战并提高翻译潜力，我们建议 将我们的治疗方法的临床前测试扩展到非人类灵长类动物(NHP)。我们要测试一下它的疗效 囊化同种异体卵巢移植启动青春期生理发育，我们将研究 移植物功能的寿命以及受者对初始和 重复植入并评估胶囊中培养的卵母细胞的质量以恢复生育能力。 如果成功，这种方法将提供一种临床上相关的和未被探索的恢复卵巢的工具 POI年轻女性的内分泌功能。 我们在去卵巢的成年小鼠模型中证明了同种异体卵巢移植物的植入 包裹在免疫隔离水凝胶胶囊中恢复正常生理内分泌 卵巢功能不会引发免疫排斥反应。然而，啮齿动物在临床上存在局限性 对人类的翻译，例如青春期前女性的小尺寸，这限制了之前的干预 青春期以及啮齿动物和人类同种免疫反应的差异。 为了克服这些挑战并增加翻译潜力，我们提出了研究建议 建议将我们的治疗方法的临床前测试扩展到非人类灵长类动物(NHP)。我们将测试 包埋式同种异体卵巢移植启动青春期青春期的有效性，我们将 研究移植物功能的寿命以及受者对初始免疫反应的动态 并重复植入，评估胶囊中培养的卵母细胞的质量，以恢复生育能力。 如果成功，这种方法将提供一种临床上相关的和未被探索的恢复卵巢的工具 POI年轻女性的内分泌功能。