Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Cancer Discov. 2013 Apr;3(4):406-17. doi: 10.1158/2159-8290.CD-12-0429. Epub 2013 Jan 28.
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.
The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.
RNA 干扰（RNAi）是一种强大且特异的基因表达调控机制。利用 RNAi 沉默与疾病相关的基因有望开发出一类新的治疗药物。递送至靶器官是实现 RNAi 潜力的关键，脂质纳米颗粒（LNP）已被证明能有效地将 siRNA 递送至肝脏和动物肿瘤部位。为了研究 LNP 包载的 siRNA 在人体中的活性和安全性，我们启动了一项针对血管内皮生长因子（VEGF）和驱动蛋白纺锤体蛋白（KSP）的 siRNA 的 LNP 制剂 ALN-VSP 在癌症患者中的试验。在此，我们在肿瘤活检中检测到药物，在肝脏中检测到 siRNA 介导的 mRNA 切割，药效学提示靶标下调，以及抗肿瘤活性，包括子宫内膜癌肝转移的完全消退。此外，我们还表明，每周两次静脉注射 ALN-VSP 是安全且耐受良好的。这些数据为人类 RNAi 治疗提供了概念验证，并为癌症的进一步开发奠定了基础。
本报告中的发现显示了一种新型首创的 LNP 包载 RNAi 治疗药物在癌症患者中的安全性、药代动力学、RNAi 作用机制和临床活性。利用 RNAi 进行特异性多靶向治疗的能力，以及增加可成药靶标的数量，对肿瘤学未来的药物开发具有重要意义。
