Development of a Novel Gastrointestinal Radiomitigator

描述(由申请人提供)：通过核事故意外暴露在辐射中，或爆炸“脏弹”，可能对人类造成毁灭性的后果。我们开发了一种新的小分子稳定的磷脂生长因子溶血磷脂酸的类似物，十八碳烯基硫代磷酸(OTP)，当在辐射暴露后至少6小时施加时，通过从致死剂量的伽玛照射中拯救小鼠的肠道和造血细胞的凋亡，显示出强大的辐射防护和放射减轻作用。OTP还可以减少腹泻和由活性氧对上皮细胞造成的屏障损伤。在这里，我们建议评估OTP在非人类灵长类动物中的作用。 根据联邦法规(CFR)关于开发十八烯基硫代磷酸酯(OTP)作为辐射防护剂/放射性增强剂面向新药应用(NDA)的法规，我们建议：1)在FDA许可的设施Avanti Polar Lipids Inc.的分包合同中，按照化学、制造和控制标准[CMC，21 CFR 321.23(A)(7)](CGMP生产)建立OTP合成。2)用CGMP生产的OTP和我们现有的非CGMP产品在小鼠身上进行有限的动物疗效比较研究。这些实验将首先通过口服和皮下应用来测试小鼠的急性毒性，然后测试LD90/30剂量的伽马辐射对小鼠的放射防护效果，并在6h后使用OTP进行治疗。3)我们将确定成年恒河猴未观察到的不良反应水平(NOAEL)是否与我们在小鼠身上测定的低毒水平(ICH指南S2A、S2B、S4A、S5A和S5B)一致。4)根据《动物疗效规则》[21 CFR 314.610]，我们将确定口服避孕药作为胃肠道放射防护剂和放射乳化剂对恒河猴的治疗效果。具体来说：a)在骨髓屏蔽模型中，从照射前1h开始，采用口服和皮下联合应用的方法，确定OTP对隐窝存活的辐射防护效果。B)在照射后6h开始口服和皮下联合应用的骨髓屏蔽模型中，确定OTP对隐窝存活的放射治疗效果。 该项目将由田纳西大学健康科学中心和加州大学戴维斯分校的加州国家灵长类研究中心密切合作进行。该项目完成后，将为向FDA提交INDA提供必要的数据，并最终为我国提供有效的肠道辐射损伤治疗。

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.