Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.
Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.
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DOI：
10.1038/mt.2008.200
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发表时间：
2008-11
影响因子：
12.4
通讯作者：
Weissman, Drew
中科院分区：
文献类型：
--
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
体外转录的mRNA编码物理上重要的蛋白质具有相当大的治疗应用潜力，但是，由于其不稳定和免疫原性，mRNA对于临床使用是不可行的。会议会增强MRNA的生物学特性。在哺乳动物细胞和裂解物中测试或以0.015-0.15 mg/kg剂量静脉注射到小鼠中时，mRNA比未经修饰的mRNA。两种产物的水平都显着较高，即使在较高剂量下给予含假氨酸的mRNA。干扰素α的水平（IFN-α）表明，核能修饰是一种有效的方法，可以增强mRNA的稳定性和翻译能力，同时减少其在体内赋予的特性。基因替代和疫苗接种。
In vitro–transcribed mRNAs encoding physiologically important proteins have considerable potential for therapeutic applications. However, in its present form, mRNA is unfeasible for clinical use because of its labile and immunogenic nature. Here, we investigated whether incorporation of naturally modified nucleotides into transcripts would confer enhanced biological properties to mRNA. We found that mRNAs containing pseudouridines have a higher translational capacity than unmodified mRNAs when tested in mammalian cells and lysates or administered intravenously into mice at 0.015–0.15 mg/kg doses. The delivered mRNA and the encoded protein could be detected in the spleen at 1, 4, and 24 hours after the injection, where both products were at significantly higher levels when pseudouridine-containing mRNA was administered. Even at higher doses, only the unmodified mRNA was immunogenic, inducing high serum levels of interferon-α (IFN-α). These findings indicate that nucleoside modification is an effective approach to enhance stability and translational capacity of mRNA while diminishing its immunogenicity in vivo. Improved properties conferred by pseudouridine make such mRNA a promising tool for both gene replacement and vaccination.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
2.3
作者：
WILCOX, KS;BUCHHALTER, J;DICHTER, MA
通讯作者：
DICHTER, MA
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G
影响因子：
14.9
作者：
Davis, DR
通讯作者：
Davis, DR
影响因子：
56.9
作者：
WOLFF, JA;MALONE, RW;FELGNER, PL
通讯作者：
FELGNER, PL