Next Generation Therapies for Fertility Preservation in Male Cancer Patients

男性癌症患者保留生育能力的下一代疗法

• 批准号: 10402370
• 负责人: Marvin L. Meistrich
• 金额: $ 79.38万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402370
• 关键词: Adult; Animals; Autologous Transplantation; Back; Bilateral; Biological; Biopsy; CSF3 gene; Cancer Model; Cancer Patient; Cancer Survivor; Cancer Survivorship; Chemotherapy and/or radiation; Cryopreservation; Cytotoxic Chemotherapy; Data; Devices; Distress; Environment; Exposure to; Failure; Fertility; Fertilization; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Freezing; Future; Gametogenesis; Goals; Granulocyte Colony-Stimulating Factor; Growth; Human; Immune; Implant; In Vitro; Individual; Infertility; Intervention; Macaca; Macaca mulatta; Male Infertility; Malignant neoplasm of testis; Medical; Methods; Microfluidic Microchips; Mind; Modeling; Monkeys; Morphology; Mus; Mutation; Natural regeneration; Non-Malignant; Oocytes; Organ Culture Techniques; Patients; Permeability; Pharmacology; Production; Puberty; Radiation induced damage; Recovery; Research; Rhesus; Risk; Scrotum; Signal Transduction; Skin; Spermatogenesis; Stem cell transplant; Techniques; Technology; Testicular Tissue; Testing; Testis; Time; Tissues; Translating; Translations; Virus; Work; base; boys; cancer cell; cancer therapy; clinically relevant; design; experimental study; fertility preservation; human tissue; iatrogenic injury; improved; irradiation; leukemia; male; male fertility; mature animal; men; neoplastic cell; next generation; novel; offspring; pre-clinical; prepuberty; preservation; programs; reproductive; sperm cell; sperm function; stem cell proliferation; stem cells; tool

Summary Medical treatments for cancer or other non-malignant conditions can cause permanent infertility. The only fertility preservation option available to prepubertal male patients who are not producing sperm is experimental testicular tissue freezing. Prepubertal boys do have spermatogonial stem cells (SSCs) in their testes that have the potential to produce sperm. With this in mind, academic centers around the world are cryopreserving testicular tissues for boys in anticipation that those tissues can be used in the future to restore fertility. Although methods to produce sperm and live offspring from immature frozen tissues have been developed in mice, translation to efficient and safe methods to produce sperm from those tissues in humans has not been achieved. We will use our rhesus macaque model of cancer survivorship to test next generation technologies that might be used to protect endogenous SSCs from gonadotoxic therapies or produce sperm and offspring from cryopreserved, prepubertal testicular tissues. In addition, each patient who preserves testicular tissues at the Fertility Preservation Program in Pittsburgh (https://fertilitypreservationpittsburgh.org/) donates a portion of their tissue to research, which will enable us to extend the studies on macaques to human. SSC transplantation is an established approach to regenerate spermatogenesis after gonadotoxic treatment, but there are limitations to this method. This application will test three alternative approaches that may circumvent some or all of these limitations. Aim 1 will test the hypothesis that co-administration of modulation of granulocyte colony stimulating factor or fibroblast growth factor signaling at or around the time of gonadotoxic treatment will enhance survival of endogenous SSCs and recovery of spermatogenesis. Aim 2 will build on our recent demonstration that cryopreserved testicular tissue from prepubertal Rhesus macaques could be autologously grafted under the back skin or scrotal skin of the same macaque or immunotolerant mice and matured to produce sperm and a healthy baby. Graft recipients in those studies were peripubertal and castrated. Since young fertility preservation patients will not be castrated and may not have tissues re- implanted until adulthood, Aim 2 will confirm that immature testicular tissues can be matured in pubertal or adult animals with intact testes. Immature human testicular tissues will also be grafted and matured in mouse and monkey hosts. The limitations of the grafting approaches are the risk of reintroducing cancer cells if the graft is done in human or exposure to xenotropic viruses if the graft is done in an animal. To circumvent these issues, Aim 3 will utilize a testicular tissue organ culture, developed by Ogawa and colleagues, to mature prepubertal testicular tissues ex vivo. This approach has not been replicated in mice or translated to other species. We propose to replicate, modify and improve the Ogawa technique and compare to other in vitro gametogenesis platforms in mice. Finally, we will determine whether prepubertal monkey or human testicular tissues can be matured to produce sperm efficiently in any of these in vitro gametogenesis platforms.

概括 癌症或其他非恶性状况的医疗治疗可能会导致永久性不育症。唯一的 未产生精子的青春期前男性患者可用的生育保存选择是实验 睾丸组织冷冻。青春期前男孩的睾丸中确实有精子干细胞（SSC） 产生精子的潜力。考虑到这一点，世界各地的学术中心都在冷冻水平 预期男孩的睾丸组织将来可以使用这些组织来恢复生育能力。 尽管在未成熟的冷冻组织中产生精子和生命后代的方法已在 小鼠，转化为有效且安全的方法，从人类中从这些组织中产生精子 成就了。我们将使用恒河猴的癌症生存模型来测试下一代技术 可能用于保护内源性SSC免受性腺毒性疗法或产生精子和后代 来自冷冻保存的，青春期前的睾丸组织。另外，每个保留睾丸组织的患者 匹兹堡的生育保存计划（https://fertilitypresevertancervitsburgh.org/）捐赠了一部分 他们的组织进行研究，这将使我们能够将猕猴的研究扩展到人类。 SSC 移植是一种既定的方法，用于在促性毒性治疗后再生精子发生，但 这种方法存在局限性。该应用程序将测试三种可能规避的替代方法 这些局限性的一些或全部。 AIM 1将检验以下假设 促性因子刺激因子或成纤维细胞生长因子信号传导或促性腺毒性时期 治疗将提高内源性SSC的存活和精子发生的恢复。 AIM 2将基于我们的 最近的证明，可能是猕猴的冷冻保存睾丸组织 自体嫁接在同一猕猴或免疫耐药小鼠的背部或阴囊皮肤下 成熟以产生精子和健康的婴儿。这些研究中的接枝接受者是腹膜和 cast割。由于年轻的生育能力保护患者不会被cast割，并且可能没有组织 AIM 2植入直到成年后，将确认未成熟的睾丸组织可以在青春期或 成年动物完整的睾丸。未成熟的人类睾丸组织也将移植并成熟在小鼠中 和猴子主持人。嫁接方法的局限性是如果 如果在动物中进行移植，则在人类中进行移植物或接触异种病毒。绕过这些 问题，AIM 3将利用Ogawa及其同事开发的睾丸组织器官培养 前体内睾丸组织。这种方法尚未在小鼠中复制或翻译成其他 物种。我们建议复制，修改和改进大瓦技术，并与其他体外进行比较 小鼠的配子发生平台。最后，我们将确定前猴子还是人睾丸 可以将组织成熟以在任何这些体外配子发生平台中有效产生精子。