Section of Internal Medicine, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona, Policlinico Giambattista Rossi, 37134, Verona, Italy.
Intern Emerg Med. 2018 Apr;13(3):313-318. doi: 10.1007/s11739-018-1810-5. Epub 2018 Mar 1.
The idea of using small RNA fragments (oligonucleotides) for therapeutic purposes dates back to the 1990s, following the landmark discoveries on the mechanisms of gene silencing and RNA-interference (RNA-i). However, the first applications in medicine were hampered by difficulties in chemical stabilization and efficient delivery to target tissues. Recent advances in chemical manipulation of oligonucleotides have, at least partially, bypassed such obstacles. In particular, conjugation with ligands for specific receptors allows the selective uptake of oligonucleotides by critical cells (e.g., hepatocytes), where they inhibit the synthesis of the target protein by binding the complementary mRNA and inducing its degradation. In parallel, next-generation sequencing (NGS) studies at population levels have identified a number of key molecular targets, mainly through the discovery of "human knock-outs," i.e., subjects lacking a given protein because of nonsense mutations in the corresponding gene. Such highly informative individuals are often healthy, or even protected from the development of certain diseases. Indeed, subjects with null mutations in certain genes controlling lipoprotein metabolism like PCSK9 or ANGPTL-3 have a lower risk of cardiovascular disease. Since the complete absence of such proteins does not appear to carry any negative health effect, the corresponding genes are ideal candidates for the silencing approach. Pilot clinical trials with long acting anti-PCSK9 or anti-ANGPTL-3 oligonucleotides have yielded very promising results, so that their use as "vaccines" against atherosclerosis has been suggested in the future. As therapeutic oligonucleotides can virtually target innumerable proteins, their increasing development is predicted to substantially expand the repertoire of the "biological drugs," in addition to, or even substituting, more consolidated approaches like monoclonal antibodies.
利用小 RNA 片段（寡核苷酸）进行治疗的想法可以追溯到 20 世纪 90 年代，当时关于基因沉默和 RNA 干扰（RNA-i）机制的重要发现问世。然而，第一批医学应用受到化学稳定性和有效递送到靶组织的困难的阻碍。寡核苷酸化学修饰的最新进展至少部分克服了这些障碍。特别是，与特定受体的配体缀合可以允许寡核苷酸被关键细胞（例如肝细胞）选择性摄取，在这些细胞中，它们通过结合互补的 mRNA 并诱导其降解来抑制靶蛋白的合成。与此同时，人群水平的下一代测序（NGS）研究通过发现“人类敲除”，即由于相应基因中的无意义突变而缺乏特定蛋白质的个体，确定了许多关键的分子靶标。这些高度信息丰富的个体通常健康，甚至免受某些疾病的发展。事实上，控制脂蛋白代谢的某些基因（如 PCSK9 或 ANGPTL-3）中存在无意义突变的个体患心血管疾病的风险较低。由于这些蛋白质的完全缺失似乎不会带来任何健康负面影响，因此相应的基因是沉默方法的理想候选者。长效抗 PCSK9 或抗 ANGPTL-3 寡核苷酸的临床试验取得了非常有希望的结果，因此有人建议将来将其用作抗动脉粥样硬化的“疫苗”。由于治疗性寡核苷酸实际上可以靶向无数种蛋白质，因此它们的不断发展预计将大大扩展“生物药物”的范围，除了或甚至替代更成熟的方法，如单克隆抗体。
