Elmén Joacim, Thonberg Håkan, Ljungberg Karl, Frieden Miriam, Westergaard Majken, Xu Yunhe, Wahren Britta, Liang Zicai, Ørum Henrik, Koch Troels, Wahlestedt Claes
Center for Genomics and Bioinformatics, Karolinska Institutet 171 77 Stockholm, Sweden.
Nucleic Acids Res. 2005 Jan 14;33(1):439-47. doi: 10.1093/nar/gki193. Print 2005.
Therapeutic application of the recently discovered small interfering RNA (siRNA) gene silencing phenomenon will be dependent on improvements in molecule bio-stability, specificity and delivery. To address these issues, we have systematically modified siRNA with the synthetic RNA-like high affinity nucleotide analogue, Locked Nucleic Acid (LNA). Here, we show that incorporation of LNA substantially enhances serum half-life of siRNA's, which is a key requirement for therapeutic use. Moreover, we provide evidence that LNA is compatible with the intracellular siRNA machinery and can be used to reduce undesired, sequence-related off-target effects. LNA-modified siRNAs targeting the emerging disease SARS, show improved efficiency over unmodified siRNA on certain RNA motifs. The results from this study emphasize LNA's promise in converting siRNA from a functional genomics technology to a therapeutic platform.
最近发现的小干扰RNA（siRNA）基因沉默现象的治疗应用将取决于分子生物稳定性、特异性和递送方面的改进。为了解决这些问题，我们用合成的类RNA高亲和力核苷酸类似物——锁核酸（LNA）对siRNA进行了系统修饰。在此，我们表明LNA的掺入显著提高了siRNA的血清半衰期，这是治疗应用的关键要求。此外，我们提供证据表明LNA与细胞内siRNA机制兼容，可用于减少不期望的、与序列相关的脱靶效应。靶向新出现疾病SARS的LNA修饰siRNA在某些RNA基序上比未修饰的siRNA表现出更高的效率。这项研究的结果强调了LNA在将siRNA从功能基因组学技术转变为治疗平台方面的前景。
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