Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, China.
Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Mol Ther. 2023 Apr 5;31(4):1106-1122. doi: 10.1016/j.ymthe.2023.01.016. Epub 2023 Jan 24.
Antisense oligonucleotide (ASO) is a major tool used for silencing pathogenic genes. For stroke in the hyperacute stage, however, the ability of ASO to regulate genes is limited by its poor delivery to the ischemic brain owing to sudden occlusion of the supplying artery. Here we show that, in a mouse model of permanent ischemic stroke, lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide (lipid-HDO) was unexpectedly delivered 9.6 times more efficiently to the ischemic area of the brain than to the contralateral non-ischemic brain and achieved robust gene knockdown and change of stroke phenotype, despite a 90% decrease in cerebral blood flow in the 3 h after occlusion. This delivery to neurons was mediated via receptor-mediated transcytosis by lipoprotein receptors in brain endothelial cells, the expression of which was significantly upregulated after ischemia. This study provides proof-of-concept that lipid-HDO is a promising gene-silencing technology for stroke treatment in the hyperacute stage.
反义寡核苷酸（ASO）是一种用于沉默致病基因的主要工具。然而，对于超急性阶段的中风，由于供应动脉突然阻塞，ASO 调节基因的能力受到其向缺血性大脑输送不良的限制。在这里，我们在永久性缺血性中风的小鼠模型中表明，脂质配体缀合的 DNA/RNA 杂合寡核苷酸（脂质-HDO）出乎意料地以比对侧非缺血性大脑高 9.6 倍的效率递送到大脑的缺血区域，尽管在闭塞后 3 小时内脑血流减少了 90%，但仍实现了强大的基因敲低和中风表型改变。这种递送至神经元是通过脑内皮细胞中的脂蛋白受体介导的受体介导的胞吞作用来实现的，这些受体的表达在缺血后显著上调。这项研究提供了概念验证，表明脂质-HDO 是一种有前途的基因沉默技术，可用于超急性阶段的中风治疗。
Zotero 插件