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，由于治疗毒性。女性癌症幸存者 POI导致不孕，以及卵巢内分泌功能的丧失，这反过来又导致早产。 骨质减少、肌肉萎缩和加速心血管疾病。这些长期影响是 这一点很重要，特别是对进入青春期的年轻女孩来说。我们的结果在一个卵巢切除的成年小鼠 模型已经证明，将卵巢同种异体移植物包封在 基于免疫隔离水凝胶的胶囊恢复正常生理内分泌卵巢功能 而不会引发免疫排斥反应然而，啮齿类动物在临床转化为人类方面存在局限性， 如1）青春期前女性的小尺寸限制了青春期前和青春期开始前的干预 在灵长类动物中的调节方式与啮齿类动物不同; 2） 小鼠卵巢具有有限的翻译潜力;和3）免疫应答的差异限制了 我们的发现的范围。为了克服这些挑战并提高翻译潜力，我们建议 将我们的疗法的临床前测试扩展到非人灵长类动物（NHP）。我们将测试 为了在青少年NHP中启动生理性青春期，我们将研究 移植物功能的寿命以及受体对初始和 重复培养并评估在胶囊中生长的卵母细胞的质量以恢复生育力。 如果成功，这种方法将提供一个临床相关的和未探索的工具，以恢复卵巢癌。 内分泌功能的年轻女性POI。 我们已经在切除卵巢的成年小鼠模型中证实， 包封在免疫隔离水凝胶胶囊中， 卵巢功能而不引起免疫排斥。然而，啮齿类动物在临床上存在局限性， 翻译到人类，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之间同种免疫反应的差异。 为了克服这些挑战并提高翻译潜力，我们 建议将我们的疗法的临床前测试扩展到非人灵长类动物（NHP）。我们将测试 为了证实卵巢移植对青春期NHP启动生理性青春期的有效性，我们将 研究移植物功能的寿命以及受体对初始免疫应答的动态， 重复培养并评估在胶囊中生长的卵母细胞的质量以恢复生育力。 如果成功，这种方法将提供一个临床相关的和未探索的工具，以恢复卵巢癌。 内分泌功能的年轻女性POI。