Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates.
Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates.
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DOI：
10.1093/nar/gkq457
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发表时间：
2010-11
影响因子：
14.9
通讯作者：
Koch T
中科院分区：
文献类型：
--
作者：
Straarup EM;Fisker N;Hedtjärn M;Lindholm MW;Rosenbohm C;Aarup V;Hansen HF;Ørum H;Hansen JB;Koch T
研究了锁定核酸(LNA)反义寡核苷酸的效价和特异性与长度和亲和力的关系。设计了针对载脂蛋白B(ApoB)的寡核苷酸，并对其进行了体外和体内研究。LNA的高亲和力使得设计短的反义寡核苷酸(12-到13-MERS)成为可能，与长的反义寡核苷酸相比，它在体外和体内都具有高的亲和力和更高的效力。较短的LNA寡核苷酸具有更高的靶向性，其生物分布和组织半衰期与较长的寡核苷酸相同。在小鼠和非人类灵长类动物中进行了针对载脂蛋白B的13聚体LNA寡核苷酸的药理学研究，数据表明，重复服用1-2 mg/kg/周的13聚体足以显著而持久地降低非高密度脂蛋白胆固醇，而不会增加血清肝脏毒性标志物。这些数据表明，在反义寡核苷酸的设计中需要考虑寡核苷酸长度作为一个参数，并且利用LNA化学可以产生具有足够靶向亲和力的有效的短寡核苷酸。总之，我们提出了一种13聚体LNA寡核苷酸，具有治疗潜力，在非人类灵长类动物中产生有益的降胆固醇效果。
The potency and specificity of locked nucleic acid (LNA) antisense oligonucleotides was investigated as a function of length and affinity. The oligonucleotides were designed to target apolipoprotein B (apoB) and were investigated both in vitro and in vivo. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both in vitro and in vivo compared to longer oligonucleotides. The short LNA oligonucleotides were more target specific, and they exhibited the same biodistribution and tissue half-life as longer oligonucleotides. Pharmacology studies in both mice and non-human primates were conducted with a 13-mer LNA oligonucleotide against apoB, and the data showed that repeated dosing of the 13-mer at 1–2 mg/kg/week was sufficient to provide a significant and long lasting lowering of non-high-density lipoprotein (non-HDL) cholesterol without increasing serum liver toxicity markers. The data presented here show that oligonucleotide length as a parameter needs to be considered in the design of antisense oligonucleotide and that potent short oligonucleotides with sufficient target affinity can be generated using the LNA chemistry. Conclusively, we present a 13-mer LNA oligonucleotide with therapeutic potential that produce beneficial cholesterol lowering effect in non-human primates.
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影响因子：
14.9
作者：
Stein CA;Hansen JB;Lai J;Wu S;Voskresenskiy A;Høg A;Worm J;Hedtjärn M;Souleimanian N;Miller P;Soifer HS;Castanotto D;Benimetskaya L;Ørum H;Koch T
通讯作者：
Koch T
影响因子：
12.4
作者：
Nishina, Kazutaka;Unno, Toshinori;Yokota, Takanori
通讯作者：
Yokota, Takanori
影响因子：
64.8
作者：
Soutschek, J;Akinc, A;Vornlocher, HP
通讯作者：
Vornlocher, HP
影响因子：
14.9
作者：
Grünweller, A;Wyszko, E;Kurreck, J
通讯作者：
Kurreck, J
影响因子：
--
作者：
Jepsen, JS;Pfundheller, HM;Lykkesfeldt, AE
通讯作者：
Lykkesfeldt, AE