siRNA药物研究进展

贺婉红,薛嫚,李芳,俸灵林,张婷

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (14) : 1145-1151.

PDF(1132 KB)
PDF(1132 KB)
中国药学杂志 ›› 2018, Vol. 53 ›› Issue (14) : 1145-1151. DOI: 10.11669/cpj.2018.14.001
综述

siRNA药物研究进展

  • 贺婉红,薛嫚,李芳,俸灵林,张婷*
作者信息 +

Research Progress of siRNA Drugs

  • HE Wan-hong, XUE Man, LI Fang, FENG Ling-lin, ZHANG Ting*
Author information +
文章历史 +

摘要

RNA干扰技术(RNAi)因其具有高效、高特异性、低毒等优点在生物医药领域方面潜力巨大,为新药的研发提供了非常好的思路。通过合理设计、化学修饰及载体可在一定程度上解决小干扰RNA(siRNA)药物快速降解、细胞摄取率低和脱靶效应等问题。笔者主要从适应证、给药方式及纳米载体等几个方面对进入临床试验的siRNA药物进行综述,为从事siRNA药物研发的研究者提供参考。

Abstract

RNA interference technology(RNAi) has a great potential in the biomedical field, providing a very good idea for the research and development of new drugs because of its high efficiency, high specificity, and low toxicity. Rational design strategies, chemical modifications and nanocarriers offer significant opportunities to overcome the deficiencies of siRNA drugs such as rapid degradation, poor cell uptake and off-target effects. Here, the research progress of some siRNA drugs which have entered clinical trials was reviewed based on their indications, administration routes and nanocarriers, which provides references for researchers in development of siRNA drugs.

关键词

小干扰RNA / 基因沉默 / 治疗应用 / 纳米载体

Key words

siRNA / gene silencing / therapeutic use / nanocarrier

引用本文

导出引用
贺婉红,薛嫚,李芳,俸灵林,张婷. siRNA药物研究进展[J]. 中国药学杂志, 2018, 53(14): 1145-1151 https://doi.org/10.11669/cpj.2018.14.001
HE Wan-hong, XUE Man, LI Fang, FENG Ling-lin, ZHANG Ting. Research Progress of siRNA Drugs[J]. Chinese Pharmaceutical Journal, 2018, 53(14): 1145-1151 https://doi.org/10.11669/cpj.2018.14.001
中图分类号: R944   

参考文献

[1] JORGENSEN R. Altered gene expression in plants due to transinteractions between homologous genes[J]. Trends Biotechnol, 1990, 8(12):340-344.
[2] FIRE A, XU S, MONTGOMERY M K,et al. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans[J]. Nature, 1998, 391(6669):806-811.
[3] ELBASHIR S M, HARBORTH J, LENDECKEL W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J]. Nature, 2001,411(6836):494-498.
[4] NAITO Y, UI-TEI K. Designing functional siRNA with reduced off-target effects[J]. Methods Mol Biol, 2013,942: 57-68.
[5] SNØVE J O, HOLEN T. Many commonly used siRNAs risk off-target activity[J]. Biochem Biophys Res Commun, 2004, 319(1):256-263.
[6] DOKKA S, TOLEDO D, SHI X, et al. Oxygen radical mediated pulmonary toxicity induced by some cationic liposomes[J]. Pharm Res, 2000, 17(5):521-525.
[7] WANG J, LU Z, WIENTJES M G, et al. Delivery of siRNA therapeutics: barriers and carriers[J]. AAPS J, 2010, 12(4):492-503.
[8] SIOUD M. Does the understanding of immune activation by RNA predict the design of safe siRNAs?[J]. Front Biosci, 2008, 13: 4379-4392.
[9] WU S Y, YANG X, GHARPURE K M, et al. 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity[J]. Nat Commun, 2014, 5:3459.
[10] OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Liposomal siRNA nanocarriers for cancer therapy[J]. Adv Drug Deliv Rev, 2014, 66:110-116.
[11] KLEINMAN M E, YAMADA K, TAKEDA A, et al. Sequence-and target-independent angiogensis suppression by siRNA via TLR3[J]. Nature, 2008, 452(7187):591-597.
[12] ALNYLAM. Complete Results of our ALN-RSV01 Phase IIb Study[EB/OL]. [2012-09-04]. http://www.alnylam.com/capella/presentations/complete-results-of-our-aln-rsv01-phase-iib-study/
[13] LEACHMAN S A, HICKERSON R P, SCHWARTZ M E, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder[J]. Mol Ther, 2010, 18(2):442-446.
[14] SYLENTIS. Sylentis announces top-line results from Phase II study SYLTAG for RNAi drug bamosiran(SYL040012) in Glaucoma[EB/OL]. [2015-10-02]. http://www.sylentis.com/index.php/en/news/professional-news/103-sylentis-announces-top-line-results-from-phase-ii-study-syltag-for-rnai-drug-bamosiran-syl040012-in-glaucoma.
[15] SYLENTIS. Sylentis reports positive Phase Ⅱ results with SYL1001 in treating ocular pain related to dry eye syndrome[EB/OL]. [2016-03-14]. http://www.sylentis.com/index.php/en/news/professional-news/108-sylentis-reports-positive-phase-ii-results-with-syl1001-in-treating-ocular-pain-related-to-dry-eye-syndrome.
[16] QUARK.Quark Pharmaceuticals Awarded Key Patent for QPI-1007 Ocular Neuroprotectant[EB/OL]. [2016-07-28]. http://quarkpharma.com/?p=12340.
[17] RIBO.The first clinical study of small necleicacid was approved in China [EB/OL]. [2015-12-25]. http://www.ribolia.com/cn/news/detail.aspx?NewsId=179&BasicClassId=509&HeadID=3.
[18] SILENSEED. Pancreatic Cancer[EB/OL]. [2017-10-22]. http://silenseed.com/?page_id=2539.
[19] BURNETT J C, ROSSI J J. RNA-based therapeutics: current progress and future prospects[J]. Chem Biol, 2012, 19(1):60-71.
[20] QUARK. Quark Pharmaceuticals Doses First Patients in Two Pivotal Phase III Studies and One Phase II Study of RNAi-Based Therapeutics for Kidney and Eye Indications[EB/OL]. [2016-3-14]. http://quarkpharma.com/?p=12305.
[21] ZUCKERMAN J E, GRITLI I, TOLCHER A, et al. Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA[J]. Proc Natl Acad Sci USA, 2014, 111(31):11449-11454.
[22] ARBUTUS. Arbutus Reports Topline Results from TKM-PLK1 HCC Clinical Trial[EB/OL]. [2016-7-19]. http://investor.arbutusbio.com/releasedetail.cfm?ReleaseID=980210.
[23] ALNYLAM. Complete Study Results from our ALN-VSP Phase I Trial and Extension Study Published in “Cancer Discovery”[EB/OL]. [2013-1-30]. http://www.alnylam.com/capella/publications/complete-study-results-from-our-aln-vsp-phase-i-trial-and-extension-study-published-in-cancer-discovery/.
[24] MEDICINES. The Medicines Company and Alnylam Pharmaceuticals Report Positive Final Results from ORION-1 Phase II Study of Inclisiran[EB/OL]. [2017-3-17]. http://www.themedicinescompany.com/investors/news/medicines-company-and-alnylam-pharmaceuticals-report-positive-final-results-orion-1.
[25] LIDDELL A M, DAVEY RT J R, MEHTA A K, et al. Characteristics and clinical management of a cluster of 3 patients with ebola virus disease, including the first domestically acquired cases in the United States[J]. Ann Intern Med, 2015,163(2):81-90.
[26] KRAFT C S, HEWLETT A L, KOEPSELL S, et al. The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States[J]. Clin Infect Dis, 2015, 61(4):496-502.
[27] ALNYLAM. Alnylam and Sanofi Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR(hATTR) Amyloidosis Patients with Polyneuropathy. [EB/OL]. [2017-9-20]. http://investors.alnylam.com/releasedetail.cfm?ReleaseID=1041081.
[28] DICERNA. Dicerna Announces Dosing of First Patient in Phase 1 Clinical Trial of DCR-PH1 in Patients with Primary Hyperoxaluria Type 1(PH1) [EB/OL]. [2016-3-13]. http://investors.dicerna.com/releasedetail.cfm?ReleaseID=970877.
[29] SILENCE.Atu027 update[EB/OL]. [2016-4-5]. http://www.silence-therapeutics.com/news-media/#page=3.
[30] OZCAN G, OZPOLAT B, COLEMAN R L, et al. Preclinical and clinical development of siRNA-based therapeutics[J]. Adv Drug Deliv Rev, 2015, 87: 108-119.
[31] TRIOZZI P, KOOSHKI M, ALISTAR A, et al. Phase I clinical trial of adoptive cellular immunotherapy with APN401 in patients with solid tumors[J]. J Immunother Cancer, 2015, 3(2):175.
[32] FIERCEBIOTECH.Alnylam plunges after deaths force it to pull PhIII blockbuster candidate revusiran[EB/OL]. [2016-10-6]. http://www.fiercebiotech.com/biotech/alnylam-plunges-after-deaths-sees-it-pull-phiii-blockbuster-candidate-revusiran.
[33] ALNYLAM. Pre-Clinical Data and Advancement of ALN-TTRsc02 for Transthyretin-Mediated Amyloidosis[EB/OL]. [2015-10-14]. http://www.alnylam.com/capella/presentations/pre-clinical-data-and-advancement-of-aln-ttrsc02/.
[34] ALNYLAM. New Exploratory Analysis Results from Fitusiran, an Investigational RNAi Therapeutic for the Treatment of Hemophilia and Rare Bleeding Disorders[EB/OL]. [2017-2-2]. http://www.alnylam.com/capella/presentations/new-exploratory-analysis-fitusiran/.
[35] ALNYLAM. Updated Results from Phase 1/2 Study of ALN-CC5 in Patients with Paroxysmal Nocturnal Hemoglobinuria(PNH)[EB/OL]. [2016-12-05]. http://www.alnylam.com/capella/presentations/aln-cc5-phase-1-2-data-ash-2016/.
[36] ALNYLAM. Updated Results from Phase 1/2 Study of ALN-CC5 in Patients with Paroxysmal Nocturnal Hemoglobinuria(PNH)[EB/OL]. [2016-12-05]. http://www.alnylam.com/capella/presentations/aln-cc5-phase-1-2-data-ash-2016/.
[37] ALNYLAM. Clinical Data from ALN-AAT and Non-Clinical Research Demonstrating Continued RNAi Platform Optimization and Leadership in the Field[EB/OL]. [2016-09-28]. http://www.alnylam.com/capella/presentations/aln-aat-data-and-rnai-platform-optimization/.
[38] ALNYLAM. Initial Results from Ongoing Phase 1/2 Study with ALN-GO1, in Development for the Treatment of Primary Hyperoxaluria Type 1[EB/OL]. [2016-09-24]. http://www.alnylam.com/capella/presentations/initial-clinical-results-from-aln-go1-for-ph1/.
[39] SIRNAOMICS. Sirnaomics Initiates a Clinical Phase IIa Study of Its Leading siRNA Therapeutic Candidate, STP705, for Treatment of Hypertrophic Scar[EB/OL]. [2017-02-06]. http://sirnaomics.hz.17uhui.com.cn/page64?article_id=490.
[40] SIRNAOMICS. BioWorld Today Reports Sirnaomics' Filing of First siRNA IND in China[EB/OL]. [2016-01-20]. http://sirnaomics.hz.17uhui.com.cn/page64?article_id=392.
[41] CLINICALTRIALS.GOV.MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT(PSCT19)[EB/OL]. [2016-03-22]. https://clinicaltrials.gov/ct2/show/NCT02528682?term=siRNA& rank=25.

基金

上海市2014年度“科技创新行动计划”生物医药领域科技支撑项目资助(14431902000);上海市科学技术委员会科研计划项目资助(14JC1492300)
PDF(1132 KB)

Accesses

Citation

Detail

段落导航
相关文章

/