Preserving Male Fertility After Cancer Therapy

癌症治疗后保持男性生育能力

• 批准号: 8676072
• 负责人: Kyle Edwin Orwig
• 金额: $ 152.46万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676072
• 关键词: Adolescent; Adoption; Adult; Affect; Age; American; American Society of Clinical Oncology; Anatomy; Animal Model; Animals; Area; Autoimmune Diseases; Autologous Transplantation; Behavior Therapy; Biological; Biological Preservation; Blood; Bone Marrow Transplantation; Cancer Patient; Cancer Survivor; Cell Therapy; Cell Transplantation; Chemicals; Child; Child health care; Childhood; Childhood Cancer Survivor Study; Clinic; Clinical Data; Communication; Country; Cryopreservation; Cytotoxic Chemotherapy; Data; Data Reporting; Development; Diagnosis; Disease; Distress; Ethics Committees; Exposure to; Family; Fathers; Fertility; Freezing; Future; Genetic; Germ Cells; Gonadal structure; Health; Hematopoietic stem cells; High Dose Chemotherapy; Hormonal; Hormones; Human; Human Cell Line; Human Development; Immune; Incidence; Individual; Infertility; Institutes; Instruction; Knowledge; Lead; Macaca mulatta; Male Infertility; Malignant Neoplasms; Methods; Modeling; Monkeys; Mus; National Institute of Child Health and Human Development; Natural regeneration; Non-Malignant; Organ Culture Techniques; Pancytopenia; Parents; Patients; Physiology; Pre-Clinical Model; Publishing; Quality of life; Radiation; Recommendation; Reporting; Reproduction; Reproductive Medicine; Reproductive Technology; Research; Research Personnel; Resources; Risk; Safety; Sampling; Science; Seminal fluid; Site; Societies; Specimen; Spermatogenesis; Spermatogonia; Stem cell transplant; Stem cells; Sterility; Sum; Survivors; Testicular Tissue; Testis; Tissue Grafts; Tissue Preservation; Tissues; Translating; Translations; Transplantation; United States; United States National Institutes of Health; Whole-Body Irradiation; base; boys; cancer therapy; chemotherapy; childhood cancer survivor; high risk; induced pluripotent stem cell; interest; irradiation; male; men; novel; patient population; pre-clinical; preclinical study; prepuberty; programs; psychologic; reproductive; safety testing; sperm cell; statistics; stem cell biology; stem cell technology; stem cell therapy; symposium

DESCRIPTION (provided by applicant): Chemotherapy and radiation treatments for cancer or other conditions can cause prolonged or permanent infertility. This is a significant human health concern because over 75,000 people under the age of 40 In the United States are diagnosed with cancer each year and most are cured. Adult men have the option to cryopreserve semen with sperm prior to gonadotoxic. This option is not available to prepubertal boys or adult male survivors who did not save a semen sample before treatment. For these patients, there are several stem cell technologies in the research pipeline that may preserve or restore fertility. Thi program project will generate pre-clinical radiation- and chemotherapy-induced models of male infertility in rhesus macaques that are relevant to human testis anatomy, physiology and pubertal development. The overall objective is to examine the long-term impacts of pre-pubertal chemotherapy and radiation exposure on stem cells and spermatogenesis and determine the potential of stem cell therapies to preserve and/or restore fertility. Proiect I (OnA/ig) will evalate the potential of spermatogonia! stem cell (SSC) transplantation and testicular tissue grafting or organ culture to regenerate spermatogenesis and/or produce functional sperm in monkeys treated with gonadotoxic agents during childhood. Proiect II (Clark/Byrne) will derive animal-specific induced pluripotent stem cells (IPSCs) and differentiate them into transplantable germline stem cells with autologous transplantation into chemo- and radiation-treated recipients. Proiect III (Meistrich/Shettv) will develop novel hormone suppression strategies to stimulate spermatogenesis from endogenous and/or transplanted SSCs after exposure to gonadotoxic agents. The Administrative Core A will coordinate communication and collegial interaction between project sites, transfer of biological specimens and data and report progress to NIH. Transplant Core B will provide high quality disease free rhesus macaques of the appropriate ages, generate irradiated and chemotherapy-treated models of male infertility and provide the expertise for germ cell transplantation into mice and monkeys. Each project site brings unique knowledge, expertise and resources to the program that are not available in composite at any ofthe individual sites or anywhere else in the country. Collectively, the project leaders will generate a substantial body of pre-clinical data on the feasibility of stem cell-based methods for preserving and/or restoring fertility of patients receiving gonadotoxic therapies. RELEVANCE (See instructions): There are currently no options to preserve the fertility of male cancer patient who are not producing sperm. Several academic centers in the US and abroad are actively freezing testicular tissue for cancer patients in anticipation that new stem cell technologies will be available in the future to restore their fertility. Pre-clinical studies are critically needed t test the safety and feasibility of experimental stem cell technologies so that they can be responsibly translated to the clinic.

描述（由申请人提供）：癌症或其他疾病的化疗和放射治疗可能导致长期或永久性不孕。这是一个重大的人类健康问题，因为在美国，每年有超过 75,000 名 40 岁以下的人被诊断出患有癌症，并且大多数已经治愈。成年男性可以选择在性腺毒性之前冷冻保存带有精子的精液。此选项不适用于在治疗前未保存精液样本的青春期前男孩或成年男性幸存者。对于这些患者来说，有几种干细胞技术正在研究中，可以保留或恢复生育能力。该项目将在恒河猴中建立临床前放疗和化疗诱导的雄性不育模型，这些模型与人类睾丸解剖学、生理学和青春期发育相关。总体目标是检查青春期前化疗和放射暴露对干细胞和精子发生的长期影响，并确定干细胞疗法保留和/或恢复生育能力的潜力。 Proiect I (OnA/ig) 将评估精原细胞的潜力！干细胞（SSC）移植和睾丸组织移植或器官培养，以在儿童期接受性腺毒性药物治疗的猴子中再生精子发生和/或产生功能性精子。 Proiect II (Clark/Byrne) 将获得动物特异性诱导多能干细胞 (IPSC)，并将其分化为可移植的生殖系干细胞，并将其自体移植到接受化疗和放射治疗的受体中。 Proiect III (Meistrich/Shetv) 将开发新的激素抑制策略，以在接触性腺毒性药物后刺激内源性和/或移植的 SSC 的精子发生。行政核心 A 将协调项目地点之间的沟通和同事互动、生物标本和数据的转移并向 NIH 报告进展情况。移植核心 B 将提供适当年龄的高质量无病恒河猴，生成经过辐射和化疗治疗的男性不育模型，并提供将生殖细胞移植到小鼠和猴子体内的专业知识。每个项目地点都为该计划带来了独特的知识、专业知识和资源，这些知识、专业知识和资源是任何单个地点或国内其他任何地方都无法提供的。项目负责人将共同生成大量临床前数据，说明基于干细胞的方法对于接受性腺毒性治疗的患者保留和/或恢复生育能力的可行性。相关性（参见说明）：目前没有任何选择可以保留不产生精子的男性癌症患者的生育能力。美国和国外的几个学术中心正在积极为癌症患者冷冻睾丸组织，预计新的干细胞技术将 以便将来恢复生育能力。迫切需要临床前研究来测试实验性干细胞技术的安全性和可行性，以便它们能够负责任地转化为临床。