Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma.
Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma.
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DOI：
10.2174/1389201019666180611093428
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发表时间：
2018
影响因子：
2.8
通讯作者：
Rossi JJ
中科院分区：
文献类型：
--
作者：
Setten RL;Lightfoot HL;Habib NA;Rossi JJ
寡核苷酸药物的开发使药物发现领域发生了革命性的变化。在这一领域，‘小’或‘短’激活RNA(SARNA)是最近发现的具有临床潜力的短双链RNA类别。Sarna促进靶基因的转录，这种现象在哺乳动物中广泛观察到，称为RNA激活(RNAa)。靶向特定基因的能力取决于Sarna的序列。因此，SARNAs的潜在临床应用是以序列特异性的方式增加靶基因的表达。基于SARNA的疗法提供了扩大“可用药基因组”的机会，包括转录因子激活和单倍体功能不全的病例。结果在这篇简短的综述中，我们描述了第一个进入临床的SARNA药物的临床前开发。这种被称为MTL-CEBPA的SARNA可以诱导转录因子CCAAT/增强子结合蛋白α(CEBPα)的表达增加，CEBP是一种肿瘤抑制因子，也是肝细胞功能的关键调节因子。MTL-CEBPA目前正在进行肝细胞癌的I期临床试验。MTL-CEBPA的临床发展将证明“概念证明”，SarNas可以为增强靶基因表达从而改善患者治疗结果的药物提供基础。
Oligonucleotide drug development has revolutionised the drug discovery field. Within this field, ‘small’ or ‘short’ activating RNAs (saRNA) are a more recently discovered category of short double-stranded RNA with clinical potential. saRNAs promote transcription from target loci, a phenomenon widely observed in mammals known as RNA activation (RNAa). The ability to target a particular gene is dependent on the sequence of the saRNA. Hence, the potential clinical application of saRNAs is to increase target gene expression in a sequence-specific man-ner. saRNA-based therapeutics present opportunities for expanding the “druggable genome” with partic-ular areas of interest including transcription factor activation and cases of haploinsufficiency. Results and In this mini-review, we describe the pre-clinical development of the first saRNA drug to enter the clinic. This saRNA, referred to as MTL-CEBPA, induces increased expression of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα), a tumour suppressor and critical regulator of hepatocyte function. MTL-CEBPA is presently in Phase I clinical trials for hepatocel-lular carcinoma (HCC). The clinical development of MTL-CEBPA will demonstrate “proof of concept” that saRNAs can provide the basis for drugs which enhance target gene expression and consequently improve treatment outcome in patients
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