Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland.
Nucleic Acids Res. 2012 Nov;40(21):10585-95. doi: 10.1093/nar/gks861. Epub 2012 Sep 18.
Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this field.
寡核苷酸在体内的递送通常被视为寡核苷酸药物成功开发的主要障碍。在对最近在晚期临床试验中评估的 26 种寡核苷酸药物进行的分析中，我们发现迄今为止，至少有一半已经证明了在人类相关细胞类型中抑制了靶 mRNA 和/或蛋白质水平，包括在肝脏、肌肉、骨髓、肺、血液和实体瘤中存在的细胞类型。总体而言，这强烈表明药物正在递送到适当的疾病组织中。引人注目的是，我们还发现，大多数寡核苷酸的药物靶点都在可成药基因组之外，代表了以前在临床环境中未研究过的新作用机制。尽管在临床中新型作用机制的失败风险很高，但药物已经验证了其中一部分靶点。虽然我们不想低估寡核苷酸体内递送的技术挑战，但在这里我们证明，对于该领域的成功，靶点选择和验证同样重要。
