Quark Pharmaceuticals, Inc., Boulder, Colorado 80301, USA.
Nucleic Acid Ther. 2012 Aug;22(4):255-64. doi: 10.1089/nat.2012.0371.
We report the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA I5NP following intravenous administration in rodents and nonhuman primates. I5NP is designed to act via the RNA interference (RNAi) pathway to temporarily inhibit expression of the pro-apoptotic protein p53 and is being developed to protect cells from acute ischemia/reperfusion injuries such as acute kidney injury that can occur during major cardiac surgery and delayed graft function that can occur following renal transplantation. Following intravenous administration, I5NP was very rapidly cleared from plasma was distributed predominantly to the kidney, with very low levels in liver and other tissues. Doses of 800 mg/kg I5NP in rodents, and 1,000 mg/kg I5NP in nonhuman primates, were required to elicit adverse effects, which in the monkey were isolated to direct effects on the blood that included a sub-clinical activation of complement and slightly increased clotting times. In the rat, no additional adverse effects were observed with a rat analogue of I5NP, indicating that the effects likely represent class effects of synthetic RNA duplexes rather than toxicity related to the intended pharmacologic activity of I5NP. Taken together, these data support clinical testing of intravenous administration of I5NP for the preservation of renal function following acute ischemia/reperfusion injury.
我们报告了合成的小干扰 RNA I5NP 在啮齿动物和非人灵长类动物静脉给药后的毒理学和药代动力学特性。I5NP 的设计目的是通过 RNA 干扰 (RNAi) 途径暂时抑制促凋亡蛋白 p53 的表达，并正在开发用于保护细胞免受急性缺血/再灌注损伤，如在大心脏手术期间发生的急性肾损伤和在肾移植后发生的延迟移植物功能。静脉给药后，I5NP 从血浆中迅速清除，主要分布在肾脏，肝脏和其他组织中的含量非常低。在啮齿动物中需要 800mg/kg 的 I5NP 剂量，在非人灵长类动物中需要 1000mg/kg 的 I5NP 剂量才能引起不良反应，在猴子中，这些不良反应仅限于对血液的直接影响，包括补体的亚临床激活和稍微增加的凝血时间。在大鼠中，用大鼠类似物 I5NP 未观察到其他不良反应，表明这些作用可能代表合成 RNA 双链体的类效应，而不是与 I5NP 的预期药理活性相关的毒性。综上所述，这些数据支持对 I5NP 进行静脉给药治疗急性缺血/再灌注损伤后肾功能的临床测试。
