Pre-clinical Trials for Female Fertility Preservation

描述（由申请人提供）：早期卵巢衰竭和不孕症是抗癌治疗的众所周知的副作用。虽然对肿瘤根除的需求是明确的，但这些治疗对非靶组织（如卵巢）的长期影响是巨大的。不幸的是，试图保留女性癌症患者的生育能力和卵巢功能，但收效甚微。在对小鼠的研究中，我们已经表明，鞘氨醇-1-磷酸（S1 P），促凋亡应激传感器神经酰胺的代谢产物，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，S1 P在受辐射的雌性小鼠中保持了正常的生育能力，并且用受S1 P保护的卵母细胞在体内受孕的后代没有显示出跨代基因组损伤的证据。通过使用人卵巢-小鼠异种移植模型，我们还表明，将S1 P直接注射到卵巢组织中可以防止体内辐射诱导的人原始和初级卵泡损失。尽管这些发现支持可以开发基于S1 P的策略来对抗不孕症和卵巢衰竭，但仍需要解决两个主要问题。首先是确定S1 P在暴露于抗癌治疗的非人灵长类动物中保护卵巢功能和生育能力的安全性和有效性。第二个是验证仅将S1 P输送到卵巢的技术，从而防止S1 P的全身可用性，这可能有利于靶向破坏的肿瘤细胞。为了实现这些目标，提出了以下具体目的：（1）确定S1 P是否可以直接施用到恒河猴卵巢中作为体内保护性腺免受放射治疗诱导的损伤的手段;（2）评价非人灵长类动物卵巢中S1 P保护免受放射治疗的卵母细胞的受精和胚胎发生能力;以及（3）评估由非人灵长类动物卵母细胞受孕的后代是否显示出繁殖性基因组损伤的证据，所述卵母细胞在体内通过S1 P保护免于放射治疗。我们工作的目标是开发安全有效的策略，用于保护体内人类卵巢免受抗癌治疗引起的副作用损伤。我们认为，本文讨论的已发表和初步数据强烈支持现在需要使用非人灵长类动物作为模型来评估S1 P在这方面的功效以及S1 P的递送机制。

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.