Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
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DOI：
10.1093/nar/gkl1071
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发表时间：
2007
影响因子：
14.9
通讯作者：
Bennett CF
中科院分区：
文献类型：
--
作者：
Swayze EE;Siwkowski AM;Wancewicz EV;Migawa MT;Wyrzykiewicz TK;Hung G;Monia BP;Bennett CF
设计了一系列含有2 ' - o -甲氧基乙基核糖（MOE）或锁定核酸（LNA）修饰的反义寡核苷酸（ASOs），以研究LNA反义寡核苷酸（ASOs）是否有可能改善基于MOE的ASO治疗方法。与含有ASOs的相应MOE相比，一些（但不是全部）含有寡核苷酸的LNA在小鼠肝脏中减少目标mRNA的效力提高了5倍。然而，通过血清转氨酶、器官重量和体重测量，它们也显示出严重的肝毒性。这种毒性对于靶向三种不同生物靶点的多个序列以及没有已知mRNA靶点的错配控制序列都是明显的。LNA处理动物组织的组织病理学评估证实肝细胞受累。早在单次给药后4天就观察到毒性。相比之下，相应的MOE ASOs在保持降低目标mRNA的能力的同时没有显示出毒性。这些研究表明，虽然LNA aso具有提高效力的潜力，但它们具有显著的肝毒性风险。
A series of antisense oligonucleotides (ASOs) containing either 2′-O-methoxyethylribose (MOE) or locked nucleic acid (LNA) modifications were designed to investigate whether LNA antisense oligonucleotides (ASOs) have the potential to improve upon MOE based ASO therapeutics. Some, but not all, LNA containing oligonucleotides increased potency for reducing target mRNA in mouse liver up to 5-fold relative to the corresponding MOE containing ASOs. However, they also showed profound hepatotoxicity as measured by serum transaminases, organ weights and body weights. This toxicity was evident for multiple sequences targeting three different biological targets, as well as in mismatch control sequences having no known mRNA targets. Histopathological evaluation of tissues from LNA treated animals confirmed the hepatocellular involvement. Toxicity was observed as early as 4 days after a single administration. In contrast, the corresponding MOE ASOs showed no evidence for toxicity while maintaining the ability to reduce target mRNA. These studies suggest that while LNA ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity.
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影响因子：
3.9
作者：
Geary, RS;Yu, RZ;Levin, AA
通讯作者：
Levin, AA
DOI：
10.1073/pnas.91.24.11762
发表时间：
1994-11-22
影响因子：
11.1
作者：
DEAN, NM;MCKAY, R
通讯作者：
MCKAY, R
影响因子：
11.4
作者：
Nanduri, S;Rahman, F;Qin, J
通讯作者：
Qin, J
影响因子：
9.8
作者：
Liang, Y;Osborne, MC;Demarest, K
通讯作者：
Demarest, K
影响因子：
3.2
作者：
Fluiter, K;Frieden, M;Baas, F
通讯作者：
Baas, F