First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
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DOI：
10.1158/2159-8290.cd-12-0429
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发表时间：
2013-04-01
期刊：
影响因子：
28.2
通讯作者：
Burris, Howard A., III
中科院分区：
文献类型：
--
作者：
Tabernero, Josep;Shapiro, Geoffrey I.;Burris, Howard A., III
RNA干扰（RNA interference，RNAi）是一种有效而特异的基因表达调控机制。利用RNAi沉默与疾病有关的基因有望开发出一类新的治疗方法。递送是实现RNAi潜力的关键，脂质纳米颗粒（LNP）已被证明可有效地将siRNA递送至动物的肝脏和肿瘤。为了检查LNP配制的siRNA在人体中的活性和安全性，我们在癌症患者中启动了ALN-VSP试验，ALN-VSP是一种靶向VEGF和驱动蛋白纺锤体蛋白（KSP）的siRNA的LNP制剂。在这里，我们展示了肿瘤活检中药物的检测，siRNA介导的肝脏mRNA切割，提示靶点下调的药效学和抗肿瘤活性，包括子宫内膜癌肝转移的完全消退。此外，我们表明，每两周静脉注射ALN-VSP是安全的，耐受性良好。这些数据为RNAi疗法在人类中提供了概念验证，并为进一步开发癌症奠定了基础。意义：本报告中的研究结果显示了安全性，药代动力学，RNAi作用机制和临床活性与一种新型的一流的LNP配制的RNAi治疗癌症患者。利用RNAi促进特异性多靶向以及增加可药物靶点数量的能力对肿瘤学未来药物开发具有重要意义。(C)2012年AACR。
RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer.SIGNIFICANCE: The findings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel first-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specific multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. (C) 2012 AACR.