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.

卵巢早衰（POI）是抗肿瘤治疗的常见并发症，如