Preserving Male Fertility After Cancer Therapy

描述(申请人提供)：癌症或其他疾病的化疗和放射治疗可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7.5万名40岁以下的人被诊断出患有癌症，其中大多数都被治愈了。成年男性可以选择在性腺激素产生之前用精子冷冻保存精液。这一选项不适用于青春期前男孩或成年男性幸存者，他们在治疗前没有保存精液样本。对于这些患者，有几种干细胞技术正在研究中，可能会保留或恢复生育能力。该计划项目将在猕猴身上产生临床前放射和化疗诱导的雄性不育模型，这些模型与人类睾丸解剖、生理和青春期发育相关。总体目标是检查青春期前化疗和辐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存和/或恢复生育能力的潜力。项目I(ONA/ig)将评估精原细胞的潜能！干细胞(SSC)移植和睾丸组织移植或器官培养，以再生精子发生和/或产生有功能的精子，在儿童时期使用性腺毒素药物治疗的猴子。项目II(Clark/Byrne)将获得动物特异性诱导多能干细胞(IPSCs)，并将其分化为可移植的生殖系干细胞，然后将其自体移植到化疗和放射治疗的接受者体内。项目III(Meistrich/Shettv)将开发新的激素抑制策略，以刺激暴露于性腺毒素药物后的内源性和/或移植的SSCs的精子生成。行政核心A将协调项目地点之间的沟通和联合互动，生物标本和数据的转移，并向国家卫生研究院报告进展情况。移植核心B将提供适当年龄的高质量无病恒河猴，产生辐射和化疗治疗的男性不育模型，并为将生殖细胞移植到小鼠和猴子身上提供专业知识。每个项目地点都为项目带来了独特的知识、专业知识和资源，而这些知识、专业知识和资源是任何一个单独的地点或该国任何其他地方都无法提供的。总体而言，项目负责人将产生大量临床前数据，说明基于干细胞的方法保存和/或恢复接受性腺激素治疗的患者生育能力的可行性。相关性(见说明书)：目前还没有保存不产生精子的男性癌症患者的生育能力的选择。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，以期新的干细胞技术将 可以在未来恢复它们的生育能力。迫切需要进行临床前研究，以测试实验性干细胞技术的安全性和可行性，以便能够负责任地将其转化为临床。

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.