Target mRNA inhibition by oligonucleotide drugs in man.
Target mRNA inhibition by oligonucleotide drugs in man.
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寡核苷酸药物中的靶向mRNA抑制。
DOI：
10.1093/nar/gks861
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发表时间：
2012-11
影响因子：
14.9
通讯作者：
Hall J
中科院分区：
文献类型：
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作者：
Lightfoot HL;Hall J
寡核苷酸体内递送通常被视为成功开发寡核苷酸药物的主要障碍。在对最近在后期临床试验中评估的26种寡核苷酸药物的分析中，我们发现迄今为止至少有一半已经证明了对人类相关细胞类型中靶mRNA和/或蛋白质水平的抑制，包括存在于肝脏，肌肉，骨髓，肺，血液和实体瘤中的那些。总的来说，这强烈暗示药物被递送到适当的疾病组织。引人注目的是，我们还发现寡核苷酸的大多数药物靶标位于可药物化基因组之外，并且代表了先前在临床环境中未研究的新作用机制。尽管新的作用机制在临床上失败的风险很高，但药物已经验证了一部分靶点。虽然不希望低估体内寡核苷酸递送的技术挑战，但在此我们证明了靶点选择和验证对于该领域的成功具有同等重要性。
Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this field.
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影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
影响因子：
168.9
作者：
Cirak, Sebahattin;Arechavala-Gomeza, Virginia;Guglieri, Michela;Feng, Lucy;Torelli, Silvia;Anthony, Karen;Abbs, Stephen;Garralda, Maria Elena;Bourke, John;Wells, Dominic J.;Dickson, George;Wood, Matthew J. A.;Wilton, Steve D.;Straub, Volker;Kole, Ryszard;Shrewsbury, Stephen B.;Sewry, Caroline;Morgan, Jennifer E.;Bushby, Kate;Muntoni, Francesco
通讯作者：
Muntoni, Francesco
影响因子：
11.5
作者：
Chia, Stephen;Dent, Susan;Eisenhauer, Elizabeth A.
通讯作者：
Eisenhauer, Elizabeth A.
影响因子：
12.4
作者：
Gauvreau, G. M.;Pageau, R.;Renzi, P. M.
通讯作者：
Renzi, P. M.
影响因子：
64.8
作者：
通讯作者：
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