Pre-clinical Trials for Female Fertility Preservation

女性生育力保存的临床前试验

• 批准号: 6718229
• 负责人: Jonathan Lee Tilly
• 金额: $ 36.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6718229
• 关键词: DNA damage; Macaca mulatta; cesarean section; cytoprotection; drug delivery systems; drug screening /evaluation; egg /ovum; embryogenesis; female; fertility; fertility promoting drug; in vitro fertilization; laparoscopy; menstrual cycle; mixed tissue /cell culture; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; ovariectomy; reproductive system disorder chemotherapy; sphingosine; therapy adverse effect

DESCRIPTION (provided by applicant): Early ovarian failure and infertility are well-known side effects of anti-cancer treatments. While the need for tumor eradication is clear, the long-term consequences of these treatments on non-target tissues, such as the ovaries, are substantial. Unfortunately, attempts to preserve fertility and ovarian function in female cancer patients have met with little success. In studies with mice, we have shown that sphingosine-1- phosphate (S1P), a metabolite of the pro-apoptotic stress sensor ceramide, completely protects the ovaries from radiation-induced damage in vivo. Long-term in vivo mating trials have further shown that S1P preserves a normal level of fertility in irradiated female mice, and that offspring conceived with oocytes protected from radiation by S1P in vivo show no evidence of transgenerational genomic damage. With the use of a human ovarian-mouse xenograft model, we have also shown that injecting S1P directly into ovarian tissue can prevent radiation-induced loss of human primordial and primary follicles in vivo. Although these findings support that S1P-based strategies could be developed to combat infertility and ovarian failure, two major points still need to be addressed. The first is to establish the safety and efficacy of S1P for preserving ovarian function and fertility in non-human primates exposed to anti-cancer treatments. The second is to validate technologies to deliver S1P only to the ovaries, thereby preventing systemic availability of S1P that could benefit the tumor cells targeted for destruction. To accomplish these goals, the following Specific Aims are proposed: (1) to determine if S1P can be administered directly into the rhesus monkey ovary as a means to protect the gonads from radiotherapy-induced damage in vivo; (2) to evaluate the competency of the oocytes protected from radiotherapy by S1P in the non-human primate ovary for fertilization and embryogenesis; and (3) to assess if offspring conceived from non-human primate oocytes protected from radiotherapy by S1P in vivo show evidence of propagated genomic damage. The goal of our work is to develop safe and effective strategies for protecting human ovaries in vivo from the side-effect damage caused by anti-cancer therapies. We believe that the published and preliminary data discussed herein strongly support the need for now evaluating the efficacy of, as well as the delivery mechanisms for, S1P in this regard using the non-human primate as a model.

描述（由申请人提供）：早期卵巢衰竭和不育是抗癌治疗的众所周知的副作用。尽管消除肿瘤的需求很明显，但这些治疗对非靶向组织（例如卵巢）的长期后果是很大的。不幸的是，女性癌症患者的生育能力和卵巢功能的尝试很少。在对小鼠的研究中，我们已经表明，链凋亡应力传感器神经酰胺的代谢物（S1P）完全保护卵巢免受体内辐射诱导的损伤。长期的体内交配试验进一步表明，S1P保留了受辐照的雌性小鼠的正常生育能力，并且在体内S1P受保护的卵母细胞构想的后代没有显示转传基因组损害的证据。通过使用人卵巢鼠异种移植模型，我们还表明，将S1P直接注入卵巢组织可以防止体内辐射引起的人类原始卵泡和原代卵泡的损失。尽管这些发现支持基于S1P的策略可以制定以抵抗不育和卵巢衰竭，但仍需要解决两个主要要点。首先是确定S1P在暴露于​​抗癌治疗的非人类灵长类动物中保留卵巢功能和生育能力的安全性和功效。第二个是验证技术仅向卵巢传递S1P，从而防止S1P的全身性可用性，从而使目标造成破坏的肿瘤细胞受益。为了实现这些目标，提出了以下特定目标：（1）确定是否可以直接将S1P施用到恒河猴卵巢中，以保护性腺免受放射治疗诱导的体内损害； （2）评估S1P在非人类灵长类动物卵巢中受精和胚胎发生的卵母细胞免受放射疗法的能力； （3）评估S1P在体内受到放射疗法保护的非人类灵长类动物卵母细胞的后代是否显示出传播基因组损伤的证据。我们工作的目的是制定安全有效的策略，以保护体内人类卵巢免受抗癌疗法造成的副作用损害。我们认为，本文讨论的已发表和初步数据强烈支持现在评估S1P在这方面使用非人类灵长类动物作为模型的S1P的疗效以及S1P的交付机制的需求。