Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR.
Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR.
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DOI：
10.1126/scitranslmed.3006840
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发表时间：
2013-11-20
影响因子：
17.1
通讯作者：
Näär AM
中科院分区：
文献类型：
--
作者：
Rottiers V;Obad S;Petri A;McGarrah R;Lindholm MW;Black JC;Sinha S;Goody RJ;Lawrence MS;deLemos AS;Hansen HF;Whittaker S;Henry S;Brookes R;Najafi-Shoushtari SH;Chung RT;Whetstine JR;Gerszten RE;Kauppinen S;Näär AM
MicroRNAs （miRNAs）调控着人类生物学的许多方面。它们主要通过种子序列（成熟miRNA序列中的2-8核苷酸）与3 ' utr碱基配对，靶向mrna进行翻译抑制或降解。许多单独的miRNA和miRNA家族共享种子序列和靶标，但在种子外的序列不同。mirna与多种人类疾病的病因学有关，因此代表了有希望的治疗靶点。然而，共享相同种子序列的不同mirna的潜在冗余和代偿作用，以及同时靶向在非种子序列中显著不同的mirna的挑战使治疗靶向方法复杂化。我们最近在哺乳动物细胞和小鼠的短期实验中证明了使用种子靶向8-mer锁定核酸（LNA）修饰的抗mir有效抑制整个miRNA家族。然而，这种方法在高等生物（如人类和非人类灵长类动物）中的长期有效性和安全性尚未确定。本研究表明，在肥胖和胰岛素抵抗的非人灵长类动物中，通过皮下递送8-mer lna修饰的抗mir药物抑制miR-33家族（胆固醇/脂质稳态的关键调节因子）导致miR-33靶点（如ABCA1）的去抑制，增加循环高密度脂蛋白-胆固醇（HDL-C），并且在108天的治疗中耐受性良好。这些发现证明了8-mer LNA-antimiR在非人类灵长类动物代谢疾病模型中对miRNA家族的有效性和安全性，表明这可能是一种可行的方法，用于治疗人类疾病中具有相同种子序列的miRNA家族。
MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base-pairing with 3’ UTRs, primarily via seed sequences (nucleotides 2-8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy and compensatory action of different miRNAs sharing the same seed sequence, and the challenge of simultaneously targeting miRNAs that differ significantly in non-seed sequences complicates therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and non-human primates, has not been determined. Here, we show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant non-human primates results in de-repression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein-cholesterol (HDL-C), and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against a miRNA family in a non-human primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.
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DOI：
10.1126/science.1189123
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Najafi-Shoushtari SH;Kristo F;Li Y;Shioda T;Cohen DE;Gerszten RE;Näär AM
通讯作者：
Näär AM
影响因子：
4.8
作者：
Gerin, Isabelle;Clerbaux, Laure-Alix;Bommer, Guido T.
通讯作者：
Bommer, Guido T.
DOI：
10.1073/pnas.1206432109
发表时间：
2012-10-23
影响因子：
11.1
作者：
Bernardo, Bianca C.;Gao, Xiao-Ming;McMullen, Julie R.
通讯作者：
McMullen, Julie R.
DOI：
10.1073/pnas.1005191107
发表时间：
2010-07-06
影响因子：
11.1
作者：
Marquart, Tyler J.;Allen, Ryan M.;Baldan, Angel
通讯作者：
Baldan, Angel
DOI：
10.1073/pnas.0404297101
发表时间：
2004-08-03
影响因子：
11.1
作者：
Chen, GX;Liang, GS;Brown, MS
通讯作者：
Brown, MS