Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences and Center for Brain Integration Research, Tokyo Medical and Dental University (TMDU), Japan.
FEBS Lett. 2020 May;594(9):1413-1423. doi: 10.1002/1873-3468.13742. Epub 2020 Feb 6.
Gapmer-type antisense oligonucleotides have not yet been approved for the treatment of central nervous system diseases, whereas steric-blocking-type antisense oligonucleotides have been well-developed for clinical use. We here characterize a new type of double-stranded oligonucleotides, overhanging-duplex oligonucleotides, which are composed of the parent gapmer and its extended complementary RNA. By intracerebroventricular injection, overhanging oligonucleotides show greater silencing potency with more efficient delivery into mouse brains than the parent single-stranded gapmer. Structure-activity relationship analyses reveal that the potency enhancement requires 13-mer or more overhanging oligonucleotides with a phosphorothioate backbone. Overhanging oligonucleotides provide a new platform of therapeutic oligonucleotides for gene modulation in the central nervous system.
间隙型反义寡核苷酸尚未被批准用于治疗中枢神经系统疾病，而空间位阻型反义寡核苷酸已得到很好的开发用于临床应用。我们在这里描述了一种新型的双链寡核苷酸，即悬垂双链寡核苷酸，它由亲本间隙型和其扩展的互补 RNA 组成。通过脑室内注射，悬垂寡核苷酸比亲本单链间隙型显示出更强的沉默效力，并且更有效地递送到小鼠大脑中。结构-活性关系分析表明，效力增强需要具有硫代磷酸酯骨架的 13 个或更多个碱基的悬垂寡核苷酸。悬垂寡核苷酸为中枢神经系统中的基因调节提供了一种新的治疗性寡核苷酸平台。
