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.

摘要 癌症或其他非恶性疾病的药物治疗可能会导致永久性不孕。唯一的 不产生精子的青春期前男性患者可以选择的生育能力保存方案是实验性的 睾丸组织冻结。青春期前的男孩在他们的睾丸中确实有精原干细胞(SSCs)， 产生精子的潜力。考虑到这一点，世界各地的学术中心正在进行超低温保存 为男孩提供睾丸组织，以期这些组织将来可以用来恢复生育能力。 尽管从未成熟的冷冻组织中生产精子和活体后代的方法已经在 小鼠，转化为有效和安全的方法来从人类的这些组织中产生精子还没有 已实现。我们将使用我们的恒河猴癌症存活率模型来测试下一代技术 这可能被用来保护内源性SSCs免受性腺激素治疗的影响，或者产生精子和后代 从冷冻保存的青春期前的睾丸组织中提取。此外，每个保留睾丸组织的患者 匹兹堡(https://fertilitypreservationpittsburgh.org/)的生育保护计划捐赠了一部分 他们的组织进行研究，这将使我们能够将对猕猴的研究扩展到人类。SSC 移植是性腺激素治疗后再生精子发生的既定方法，但 这种方法有其局限性。此应用程序将测试三种替代方法，它们可能会规避 这些限制的一部分或全部。目标1将检验这样的假设，即共同管理的调制 粒细胞集落刺激因子或成纤维细胞生长因子在性腺毒性时或前后的信号转导 治疗将促进内源性SSCs的存活和精子发生的恢复。Aim 2将建立在我们的 最近的证据表明，冷冻保存的青春期前猕猴的睾丸组织可能是 在同一只猕猴或免疫耐受小鼠的背部皮肤或阴囊皮肤下自体移植，并 成熟后可以产生精子和一个健康的婴儿。这些研究中的移植物接受者是青春期和 被阉割了。由于年轻的保留生育能力的患者将不会被阉割，也可能不会有组织再生. 植入到成年，Aim 2将证实未成熟的睾丸组织可以在青春期或 拥有完整睾丸的成年动物。未成熟的人类睾丸组织也将被移植并在小鼠体内成熟 和猴子的主人。移植方法的局限性在于，如果移植的细胞 移植物是在人类身上进行的，如果是在动物身上进行的，那么就是暴露在异嗜性病毒中。为了绕过这些 问题，Aim 3将利用小川和他的同事开发的睾丸组织器官培养来成熟 体外培养的青春期前睾丸组织。这种方法还没有在小鼠身上复制，也没有翻译到其他 物种。我们建议复制、修改和改进Ogawa技术，并与其他体外技术进行比较 小鼠的配子发生平台。最后，我们将确定青春期前的猴子或人类的睾丸 在任何一种体外配子发生平台上，组织都可以成熟以高效地产生精子。