Antithrombotic Effect of Antisense Factor XI Oligonucleotide Treatment in Primates
Antithrombotic Effect of Antisense Factor XI Oligonucleotide Treatment in Primates
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DOI：
10.1161/atvbaha.113.301282
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发表时间：
2013-07-01
影响因子：
8.7
通讯作者：
Monia, Brett P.
中科院分区：
文献类型：
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作者：
Crosby, Jeffrey R.;Marzec, Ulla;Monia, Brett P.
目的凝血过程中，凝血因子IX(FIX)通过FVIIa和Fxia两种不同的激活机制被激活。这两种凝血因子都可能导致血栓形成；然而，FXI在止血方面的作用有限。因此，FXI的治疗靶向可能产生相对较低的止血风险的抗血栓作用。方法和结果我们已经报道，用FXI反义寡核苷酸降低FXI水平在小鼠体内产生抗血栓活性，给灵长类动物注射FXI反义寡核苷酸可以剂量依赖和时间依赖的方式降低循环FXI水平和活性。在这里，我们评估了血栓形成和止血的狒狒模型中血浆FXI水平和血栓形成能力之间的关系。在以前对该模型的研究中，抗体诱导的抑制FXI产生了强大的抗血栓作用。在本文中，反义寡核苷酸介导的FXI血浆水平降低50%可以在不增加出血风险的情况下产生明显和持续的抗血栓作用。结论这些结果表明，使用反义寡核苷酸降低FXI水平是一种很有前途的直接抑制FXI的替代方法，并且靶向FXI可能比传统的抗血栓治疗更安全，因为传统的抗血栓治疗可以显著损害一次止血。
ObjectiveDuring coagulation, factor IX (FIX) is activated by 2 distinct mechanisms mediated by the active proteases of either FVIIa or FXIa. Both coagulation factors may contribute to thrombosis; FXI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk.Approach and ResultsWe have reported that reducing FXI levels with FXI antisense oligonucleotides produces antithrombotic activity in mice, and that administration of FXI antisense oligonucleotides to primates decreases circulating FXI levels and activity in a dose-dependent and time-dependent manner. Here, we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present article, antisense oligonucleotides-mediated reduction of FXI plasma levels by 50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding.ConclusionsThese results indicate that reducing FXI levels using antisense oligonucleotides is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis.