Heestermans Marco, van Vlijmen Bart J M
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.
Thromb J. 2017 Mar 7;15:7. doi: 10.1186/s12959-017-0130-8. eCollection 2017.
Small interfering (si) RNAs and antisense oligonucleotides (ASOs; here for simplicity reasons, both referred to as oligonucleotides) are small synthetic RNA or DNA molecules with a sequence complementary to a (pre)mRNA. Although the basic mechanisms of action between siRNAs and ASO are distinct, a sequence-specific interaction of the both oligonucleotides with the target (pre)mRNA alters the target's fate, which includes highly effective sequence-specific blockade of translation and consequently depletion of the corresponding protein. For a number of years, these oligonucleotides have been used as a tool in biological research to study gene function in vitro. More recently, safe and specific delivery of these oligonucleotides to the liver of mammals has been achieved and optimized. This not only allowed their use for in vivo gene studies in physiology and disease, but also opened the opportunity for the development of a new generation of RNA-specific drugs for therapeutic purposes. In 2013, the first oligonucleotide product targeting RNA from the hepatic cholesterol pathway was approved. For blood coagulation, a large portion of key proteins are produced in the liver, and thereby siRNAs and ASOs can also be used as appropriate tools to target these proteins in vivo. In this review, we describe the first use of oligonucleotides for this purpose from zebrafish to primates. As the use of oligonucleotides allows avoidance of early lethality associated with full deficiency of several coagulation factors, it has proved to be of value for studying these proteins in physiology and disease. Currently, oligonucleotides are tested as therapeutics, with the ultimate goal to beneficially modulate the hemostatic balance in thrombosis and hemophilia patients. We discuss both the preclinical and clinical studies of a number of siRNAs and ASOs with the potential to be introduced as drugs for prophylactic and/or treatment of thrombosis or hemophilia. We conclude that for the coagulation field, oligonucleotides are of value for research purposes, and now the moment has come to fulfill their promise as therapeutics.
小干扰（si）RNA和反义寡核苷酸（ASO；出于简化原因，此处两者均称为寡核苷酸）是与（前）mRNA序列互补的小型合成RNA或DNA分子。尽管siRNA和ASO之间的基本作用机制不同，但这两种寡核苷酸与靶标（前）mRNA的序列特异性相互作用会改变靶标的命运，其中包括对翻译进行高效的序列特异性阻断，从而导致相应蛋白质的消耗。多年来，这些寡核苷酸一直被用作生物学研究中的工具，以在体外研究基因功能。最近，已实现并优化了将这些寡核苷酸安全、特异性地递送至哺乳动物肝脏的方法。这不仅使它们可用于生理学和疾病的体内基因研究，还为开发用于治疗目的的新一代RNA特异性药物提供了机会。2013年，首个靶向肝脏胆固醇途径RNA的寡核苷酸产品获批。对于血液凝固而言，大部分关键蛋白质在肝脏中产生，因此siRNA和ASO也可作为在体内靶向这些蛋白质的合适工具。在本综述中，我们描述了从斑马鱼到灵长类动物首次将寡核苷酸用于此目的的情况。由于使用寡核苷酸可避免与几种凝血因子完全缺乏相关的早期致死性，因此已证明其在研究这些蛋白质的生理学和疾病方面具有价值。目前，寡核苷酸正在作为治疗药物进行测试，最终目标是有益地调节血栓形成和血友病患者的止血平衡。我们讨论了一些有潜力作为预防和/或治疗血栓形成或血友病药物引入的siRNA和ASO的临床前和临床研究。我们得出结论，对于凝血领域而言，寡核苷酸在研究方面具有价值，现在已到了实现其作为治疗药物的前景的时候了。
