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: 10165774
• 负责人: Marvin L. Meistrich
• 金额: $ 79.17万
• 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/10165774
• 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 癌症或其他非恶性疾病的药物治疗可能会导致永久性不孕。唯一的 对于不产生精子的青春期前男性患者可用的生育力保存选项尚处于实验阶段 睾丸组织冷冻。青春期前男孩的睾丸中确实含有精原干细胞（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进行冷冻保存 男孩的睾丸组织，预计这些组织将来可以用来恢复生育能力。 尽管已经开发出从不成熟的冷冻组织中产生精子和活体后代的方法 在小鼠中，尚未转化为从人类这些组织中产生精子的有效且安全的方法 实现了。我们将使用恒河猴癌症生存模型来测试下一代技术 可用于保护内源性 SSC 免受性腺毒性治疗或产生精子和后代 来自冷冻保存的青春期前睾丸组织。此外，每位保存睾丸组织的患者 匹兹堡生育力保存计划 (https://fertilitypreservationpittsburgh.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 移植是性腺毒性治疗后再生精子发生的一种既定方法，但是 这种方法有局限性。该应用程序将测试三种可能规避的替代方法 这些限制的部分或全部。目标 1 将检验以下假设：共同管理调节 性腺毒性发生时或前后的粒细胞集落刺激因子或成纤维细胞生长因子信号传导 治疗将增强内源性 SSC 的存活和精子发生的恢复。目标 2 将建立在我们的 最近的研究表明，来自青春期前恒河猴的冷冻睾丸组织可以 自体移植到同一猕猴或免疫耐受小鼠的背部皮肤或阴囊皮肤下， 成熟后可产生精子和健康的婴儿。这些研究中的移植受者均处于青春期 被阉割了。由于年轻的生育力保留患者不会被阉割，也可能不会进行组织再造。 植入直至成年，目标 2 将确认未成熟的睾丸组织可以在青春期或 具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到小鼠体内并成熟 和猴子主人。移植方法的局限性是如果移植方法存在重新引入癌细胞的风险 移植是在人类身上进行的，或者如果移植是在动物身上进行的，则暴露于异种病毒。为了规避这些 问题，Aim 3 将利用小川及其同事开发的睾丸组织器官培养物来成熟 青春期前睾丸组织离体。这种方法尚未在小鼠身上复制或转化为其他 物种。我们建议复制、修改和改进小川技术，并与其他体外技术进行比较 小鼠配子发生平台。最后，我们将确定青春期前的猴子还是人类的睾丸 组织可以在任何这些体外配子发生平台中成熟以有效地产生精子。