Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery
Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery
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DOI：
10.1016/j.jconrel.2010.02.011
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发表时间：
2010-06-01
影响因子：
10.8
通讯作者：
Sah, Dinah W. Y.
中科院分区：
文献类型：
--
作者：
Chen, Qingmin;Butler, David;Sah, Dinah W. Y.
小干扰RNA(SiRNA)与亲脂分子的偶联已被证明在细胞培养中提高细胞摄取，并在全身给药后在肝脏和在直接局部注射后在神经元中产生有效的内源性基因沉默。在这里，我们通过靶向少突胶质细胞中的CNPase(2‘-3’-环核苷酸3‘-磷酸二酯酶)来评估与不同连接物连接的siRNAs对胆固醇的体内递送。与未结合的siRNA相比，通过实质内注射中枢神经系统(CNS)的方式将胆固醇结合的siRNAs注射到大鼠的穹隆体内，显示出更好的沉默能力。此外，使用可切割的二硫键连接物将siRNA与胆固醇偶联，似乎有利于提高体内少突胶质细胞中CNPase mRNA的沉默效力。综上所述，这些发现表明，胆固醇结合的siRNAs可以有效地将CNS直接运送到少突胶质细胞，并且生物可切割的二硫键连接物似乎有利于提高体内靶mRNA的沉默效力。(C)2010爱思唯尔B.V.保留所有权利。
Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2'-3'-cyclic nucleotide 3'-phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo. (C) 2010 Elsevier B.V. All rights reserved.