Development of a Novel Gastrointestinal Radiomitigator

描述（由申请人提供）：核事故或“脏弹”爆炸造成的意外辐射暴露可能对人类造成毁灭性后果。我们开发了一种新的小分子量稳定的类似物的磷脂生长因子溶血磷脂酸，十八烯基硫代磷酸盐（OTP），显示出强大的辐射防护和radiomitigating行动，拯救肠和造血细胞凋亡的小鼠照射致死剂量的γ-射线照射时，应用辐射暴露后至少6小时。OTP还减少腹泻和由活性氧物质对上皮引起的屏障损伤。在这里，我们建议在非人灵长类动物中评估OTP。 根据联邦法规（CFR），将十八烯基硫代磷酸盐（OTP）作为辐射防护剂/辐射引发剂开发为新药申请（NDA），我们建议：1）按照化学、生产和控制标准[CMC，21 CFR 321 .23（a）（7）]（CGMP生产），在Avanti Polar Lipids Inc.的工厂中建立OTP合成。一家FDA许可的机构2)在小鼠中使用CGMP生产的OTP和我们目前拥有的非CGMP产品进行有限的动物疗效比较研究。这些实验将首先使用小鼠经口和皮下应用测试急性毒性，其次，测试用LD 90/30剂量的γ-辐射照射并在事后6小时用OTP处理的小鼠中的辐射刺激作用。3)我们将确定成年恒河猴中的无明显不良作用水平（NOAEL）是否与我们在小鼠中确定的低毒性一致（ICH指南S2 A、S2 B、S4 A、S5 A和S5 B）。4)我们将根据动物疗效规则[21 CFR 314.610]，确定OTP作为胃肠道放射防护剂和放射激动剂在恒河猴中的治疗疗效。具体而言：a）使用组合的口服和皮下应用，从照射前1小时开始，测定OTP对骨髓屏蔽模型中隐窝存活的辐射防护功效。B）使用组合的口服和皮下施用，在照射后6小时开始，测定OTP对骨髓屏蔽模型中隐窝存活的放射性刺激功效。 该项目将在田纳西大学健康科学中心和加州戴维斯大学的加州国家灵长类动物研究中心的密切合作下进行。该项目完成后将提供向FDA提交INDA所需的数据，并最终为我国提供有效的肠道辐射损伤治疗方法。

DESCRIPTION (provided by applicant): Unintended exposure to radiation via a nuclear accident, or explosion of a "dirty bomb," can have devastating consequences to humankind. We developed a novel small molecular weight stable analog of the phospholipid growth factor lysophosphatidic acid, octadecenyl thiophosphate (OTP) that shows strong radioprotective and radiomitigating actions by rescuing intestinal and hemopoietic cells from apoptosis in mice irradiated with lethal doses of gamma-irradiation when applied at least up to 6 hours after radiation exposure. OTP also reduces diarrhea and barrier damage induced by reactive oxygen species to the epithelium. Here we propose to evaluate OTP in non-human primates. Following the Code of Federal Regulation (CFR) for the development of octadecenyl thiophosphate (OTP) as a radioprotector/radiomitigator toward a new drug application (NDA) here we propose to: 1) Set up OTP synthesis following the standards for chemistry, manufacturing and controls [CMC, 21 CFR 321 .23(a)(7)] (CGMP production) in a subcontract by Avanti Polar Lipids Inc.-an FDA licensed facility. 2) Conduct a limited comparative animal efficacy study in mice with the CGMP-manufactured OTP and the non-CGMP product we currently have. These experiments will first test acute toxicity using oral and subcutaneous application in mice and second, test the radiomitigating effect in mice irradiated with LD90/30 dose of gamma-radiation and treated with OTP 6h post hoc. 3) We will determine whether the no-observable adverse effect level (NOAEL) in adult Rhesus macaques is consistent with the low toxicity we determined in mice (ICH guidance S2A, S2B, S4A, S5A & S5B). 4) We will determine the therapeutic efficacy of OTP as a gastrointestinal radioprotectant and radiomitigator in Rhesus macaques following the Animal Efficacy Rule [21 CFR 314.610]. Specifically: a) Determine the radioprotective efficacy of OTP on crypt survival in the bone marrow shielding model using combined oral and subcutaneous application starting 1 h pre-irradiation. b) Determine the radiomitigating efficacy of OTP on crypt survival in the bone marrow shielding model using combined oral and subcutaneous application starting 6 h post-irradiation. This project will be conducted in close collaboration between the University of Tennessee Health Science Center and the California National Primate Research Center at the University of California Davis. The project when completed will provide data necessary for filing an INDA with the FDA and ultimately provide our country with an effective treatment for radiation injury to the gut.