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首页> 外文期刊>Nucleic Acid Therapeutics >Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin
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Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin

机译：用有义寡核苷酸解毒剂逆转反义寡核苷酸活性：靶向凝血酶原的概念证明。

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The tissue half-life of second-generation antisense oligonucleotide drugs (ASOs) is generally longer than traditional small molecule therapeutics. Thus, a strategy to reverse the activity of antisense drugs is warranted in certain settings. In this study, we describe a strategy employing the administration of a complementary sense oligonucleotide antidote (SOA). As a model system we have chosen to target the coagulation factor and antithrombotic drug target, prothrombin, to assess the feasibility of this approach. ASO targeting mouse prothrombin specifically suppressed >90% hepatic prothrombin mRNA levels and circulating prothrombin protein in mice. These effects were dose- and time-dependent, and as expected produced predictable increases in anticoagulation activity [prothrombin time/activated partial thromboplastin time (PT/aPTT)]. Treatment with prothrombin SOAs resulted in a dose-dependent reversal of ASO activity, as measured by a return in prothrombin mRNA levels and thrombin activity, and normalization of aPTT and PT. The antithrombotic activity of prothrombin ASOs was demonstrated in a FeCl3-induced thrombosis mouse model, and as predicted for this target, the doses required for antithrombotic activity were also associated with increased bleeding. Treatment with SOA was able to prevent prothrombin ASO-induced bleeding in a dose-dependent manner. These studies demonstrate for the first time the utility of SOAs to selectively and specifically reverse the intracellular effects of an antisense therapy.
机译：第二代反义寡核苷酸药物（ASO）的组织半衰期通常比传统的小分子疗法更长。因此，在某些情况下必须采取逆转反义药物活性的策略。在这项研究中，我们描述了一种使用互补正义寡核苷酸解毒剂（SOA）的管理策略。作为模型系统，我们选择了针对凝血因子和抗血栓药物的靶标凝血酶原，以评估这种方法的可行性。靶向小鼠凝血酶原的ASO可特异性抑制小鼠中> 90％的肝凝血酶原mRNA水平和循环凝血酶原蛋白。这些作用是剂量和时间依赖性的，并且预期会产生可预期的抗凝活性增加[凝血酶原时间/活化的部分凝血活酶时间（PT / aPTT）]。凝血酶原SOA的治疗导致ASO活性的剂量依赖性逆转，这通过凝血酶原mRNA水平和凝血酶活性的恢复以及aPTT和PT的标准化来衡量。在FeCl3诱导的血栓形成小鼠模型中证明了凝血酶原ASO的抗血栓形成活性，并且正如对此目标所预测的，抗血栓形成活性所需的剂量也与出血增加有关。 SOA处理能够以剂量依赖的方式预防凝血酶原ASO诱导的出血。这些研究首次证明了SOA在选择性和特异性逆转反义疗法的细胞内作用方面的实用性。

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