首例RNA干扰药物问世及该领域技术演化历程
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摘要
近期,RNA干扰(RNAi)制药公司Alnylam开发的小干扰RNA (siRNA)药物ONPATTRO?美国食品与药物管理局和欧盟委员会批准上市,用于治疗成人患者的遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病变.这是全球第一款RNAi药物,该事件标志着人类继小分子化合物、单克隆抗体蛋白类药物后,在前沿生物制药领域实现了新的突破,意味着RNAi疗法从基础研究到临床治疗的开发全过程首次贯通,具有里程碑式的意义.本文概述了该药物及适应症的基本情况,介绍了RNAi发现历史、作用机理与药物特征,RNAi药物的研发历程,以及该领域关键技术的最新研究进展.
Recently, the United States Food and Drug Administration(FDA) and the European Commission(EC)approved ONPATTRO ?(Patisiran) lipid complex injection, an RNA interference(RNAi) therapeutic developed by Alnylam Pharmaceuticals, Inc., for the treatment of the polyneuropathy of hereditary transthyretin-mediated(hATTR) amyloidosis in adults. ONPATTRO is the first approved RNAi therapeutics all over the world, indicating the whole development processes have been well established. It also means a novel form of drug molecule comes to beside from bench, following the small molecules and monoclonal antibodies. Based on this milestone achievement, the basic information of the drug and indication, the mechanism and properties of RNAi therapeutics, its complicated development history, as well as the latest advances of delivery and modification technologies, were thoroughly reviewed and discussed in this paper, which provides a rough picture for ONPATTRO and RNAi therapy.
Recently, the United States Food and Drug Administration(FDA) and the European Commission(EC)approved ONPATTRO ?(Patisiran) lipid complex injection, an RNA interference(RNAi) therapeutic developed by Alnylam Pharmaceuticals, Inc., for the treatment of the polyneuropathy of hereditary transthyretin-mediated(hATTR) amyloidosis in adults. ONPATTRO is the first approved RNAi therapeutics all over the world, indicating the whole development processes have been well established. It also means a novel form of drug molecule comes to beside from bench, following the small molecules and monoclonal antibodies. Based on this milestone achievement, the basic information of the drug and indication, the mechanism and properties of RNAi therapeutics, its complicated development history, as well as the latest advances of delivery and modification technologies, were thoroughly reviewed and discussed in this paper, which provides a rough picture for ONPATTRO and RNAi therapy.
引文
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[2]Crooke S T,Witztum J L,Bennett C F,et al.RNA-targeted therapeutics.Cell Metab,2018,27(4):714-739.
[3]Hoy S M.Patisiran:first global approval.Drugs,2018,78(15):1625-1631
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[8]Benson M D,Waddington-Cruz M,Berk J L,et al.Inotersen treatment for patients with hereditary transthyretin amyloidosis.NEngl J Med,2018,379(1):22-31
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[15]Guo S,Kemphues K J.par-1,a gene required for establishing polarity in C.elegans embryos,encodes a putative Ser/Thr kinase that is asymmetrically distributed.Cell,1995,81(4):611-620
[16]Elbashir S M,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411(6836):494-498
[17]Martinez J,Patkaniowska A,Urlaub H,et al.Single-stranded antisense si RNAs guide target RNA cleavage in RNAi.Cell,2002,110(5):563-574
[18]Mcmanus M T,Sharp P A.Gene silencing in mammals by small interfering RNAs.Nature Reviews Genetics,2002,3(10):737-747
[19]Lee Y,Ahn C,Han J,et al.The nuclear RNase III Drosha initiates micro RNA processing.Nature,2003,425(6956):415-419.
[20]Kim V N.Micro RNA biogenesis:coordinated cropping and dicing.Nat Rev Mol Cell Biol,2005,6(5):376-385
[21]Meister G,Tuschl T.Mechanisms of gene silencing by doublestranded RNA.Nature,2004,431(7006):343-349
[22]Lund E,Guttinger S,Calado A,et al.Nuclear export of micro RNAprecursors.Science,2004,303(5654):95-98
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[26]Rupaimoole R,Slack F J.Micro RNA therapeutics:towards a new era for the management of cancer and other diseases.Nat Rev Drug Discov,2017,16(3):203-222
[27]Garba A O,Mousa S A.Bevasiranib for the treatment of wet,agerelated macular degeneration.Ophthalmol Eye Dis,2010,2:75-83
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[29]Robbins M,Judge A,Maclachlan I.si RNA and innate immunity.Oligonucleotides,2009,19(2):89-102
[30]Whitehead K A,Langer R,Anderson D G.Knocking down barriers:advances in si RNA delivery.Nat Rev Drug Discov,2009,8(2):129-138
[31]Krieg A M.Is RNAi dead?Mol Ther,2011,19(6):1001-1002
[32]Davis M E,Zuckerman J E,Choi C H,et al.Evidence of RNAi in humans from systemically administered si RNA via targeted nanoparticles.Nature,2010,464(7291):1067-1070
[33]Coelho T,Adams D,Silva A,et al.Safety and efficacy of RNAi therapy for transthyretin amyloidosis.N Engl J Med,2013,369(9):819-829
[34]Nair J K,Willoughby J L,Chan A,et al.Multivalent N-acetylgalactosamine-conjugated si RNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing.J Am Chem Soc,2014,136(49):16958-16961
[35]Foster D J,Brown C R,Shaikh S,et al.Advanced si RNA designs further improve in vivo performance of Gal NAc-si RNAconjugates.Mol Ther,2018,26(3):708-717
[36]Hayden E C.RNA interference rebooted.Nature,2014,508(7497):443
[37]Wu S Y,Lopez-Berestein G,Calin G A,et al.RNAi therapies:drugging the undruggable.Sci Transl Med,2014,6(240):240ps247
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[39]Garber K.Alnylam terminates revusiran program,stock plunges.Nature Biotechnology,2016,34(12):1213-1214
[40]Arrowhead.Arrowhead Pharmaceuticals Focuses Resources on Subcutaneous and Extra-Hepatic RNAi Therapeutics.http://ir.arrowheadpharma.com/static-files/c0ce7c76-51a9-41a6-9a5d-4cc8d6a94dc8.2016,1-2.
[41]Mirna.Mirna Therapeutics Halts Phase 1 Clinical Study of MRX34.https://www.businesswire.com/news/home/20160920006814/en/Mirna-Therapeutics-Halts-Phase-1-Clinical-Study.2016,1-2.
[42]Jayaraman M,Ansell S M,Mui B L,et al.Maximizing the potency of si RNA lipid nanoparticles for hepatic gene silencing in vivo.Angew Chem Int Ed Engl,2012,51(34):8529-8533
[43]Akinc A,Querbes W,De S,et al.Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.Mol Ther,2010,18(7):1357-1364
[44]Akinc A,Zumbuehl A,Goldberg M,et al.A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.Nat Biotechnol,2008,26(5):561-569
[45]Semple S C,Akinc A,Chen J,et al.Rational design of cationic lipids for si RNA delivery.Nat Biotechnol,2010,28(2):172-176
[46]Dong Y,Love K T,Dorkin J R,et al.Lipopeptide nanoparticles for potent and selective si RNA delivery in rodents and nonhuman primates.Proc Natl Acad Sci U S A,2014,111(11):3955-3960
[47]Morrissey D V,Lockridge J A,Shaw L,et al.Potent and persistent in vivo anti-HBV activity of chemically modified si RNAs.Nat Biotechnol,2005,23(8):1002-1007
[48]Huang Y.Preclinical and clinical advances of Gal NAc-decorated nucleic acid therapeutics.Mol Ther Nucleic Acids,2017,6:116-132
[49]Huang Y Y,Liang Z C.Asialoglycoprotein receptor and its application in liver-targeted drug delivery.Prog Biochem Biophys,2015,42(6):501-510
[50]Janas M M,Schlegel M K,Harbison C E,et al.Selection of Gal NAc-conjugated si RNAs with limited off-target-driven rat hepatotoxicity.Nat Commun,2018,9(1):723
[51]Arrowhead.Compositions and Methods for Inhibiting Gene Expression of Factor XII:World Intellectual Property Organization,WO2016149331:1-137.2016-09-22
[52]Khvorova A,Watts J K.The chemical evolution of oligonucleotide therapies of clinical utility.Nat Biotechnol,2017,35(3):238-248
[53]Craig K,Abrams M,Amiji M.Recent preclinical and clinical advances in oligonucleotide conjugates.Expert Opin Drug Deliv,2018,15(6):629-640
[54]Chen C,Yang Z,Tang X.Chemical modifications of nucleic acid drugs and their delivery systems for gene-based therapy.Med Res Rev,2018,38(3):829-869
[55]Hudson A J,Lee W,Porter J,et al.Stability of antisense oligonucleotides during incubation with a mixture of isolated lysosomal enzymes.International Journal of Pharmaceutics,1996,133(1-2):257-263
[56]Alnylam.Phase 1 study of ALN-TTRsc02,a subcutaneously administered investigational RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis.http://www.alnylam.com/wp-content/uploads/2018/03/10.-TTR-SCO2_FINAL.pdf.2018,1-1
[57]Janas M M,Harbison C E,Perry V K,et al.The nonclinical safety profile of Gal NAc-conjugated RNAi therapeutics in subacute studies.Toxicol Pathol,2018,46(7):735-745
[58]Zlatev I,Castoreno A,Brown C R,et al.Reversal of si RNA-mediated gene silencing in vivo.Nat Biotechnol,2018,36(6):509-511
[59]Alnylam.Alnylam R&D Day 2018.https://www.alnylam.com/wp-content/uploads/2018/12/RD_Day2018_FINAL_Capella.pdf.2018,1-236
[60]Arrowhead.Investor and Analyst R&D Day 2018.http://ir.arrowheadpharma.com/static-files/b671502e-ce6a-4346-9b83-00a366789816.2018,1-122
[2]Crooke S T,Witztum J L,Bennett C F,et al.RNA-targeted therapeutics.Cell Metab,2018,27(4):714-739.
[3]Hoy S M.Patisiran:first global approval.Drugs,2018,78(15):1625-1631
[4]Garber K.Alnylam launches era of RNAi drugs.Nat Biotechnol,2018,36(9):777-778
[5]Ando Y,Coelho T,Berk J L,et al.Guideline of transthyretinrelated hereditary amyloidosis for clinicians.Orphanet J Rare Dis,2013,8:31
[6]Gertz M A.Hereditary ATTR amyloidosis:burden of illness and diagnostic challenges.Am J Manag Care,2017,23(7Suppl):S107-S112
[7]Adams D,Gonzalez-Duarte A,O'riordan W D,et al.Patisiran,an RNAi therapeutic,for hereditary transthyretin amyloidosis.NEngl J Med,2018,379(1):11-21
[8]Benson M D,Waddington-Cruz M,Berk J L,et al.Inotersen treatment for patients with hereditary transthyretin amyloidosis.NEngl J Med,2018,379(1):22-31
[9]Keam S J.Inotersen:first global approval.Drugs,2018,78(13):1371-1376
[10]Scott L J.Tafamidis:a review of its use in familial amyloid polyneuropathy.Drugs,2014,74(12):1371-1378
[11]Plante-Bordeneuve V,Lin H,Gollob J,et al.An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy.Expert Opin Pharmacother,2018,doi:10.1080/14656566.14652018.11554648
[12]Maurer M S,Schwartz J H,Gundapaneni B,et al.Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med,2018,379(11):1007-1016
[13]Napoli C,Lemieux C,Jorgensen R.Introduction of a chimeric chalcone synthase gene into petunia results in reversible cosuppression of homologous genes in trans.Plant Cell,1990,2(4):279-289
[14]Romano N,Macino G.Quelling:transient inactivation of gene expression in Neurospora crassa by transformation with homologous sequences.Molecular Microbiology,1992,6(22):3343-3353
[15]Guo S,Kemphues K J.par-1,a gene required for establishing polarity in C.elegans embryos,encodes a putative Ser/Thr kinase that is asymmetrically distributed.Cell,1995,81(4):611-620
[16]Elbashir S M,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411(6836):494-498
[17]Martinez J,Patkaniowska A,Urlaub H,et al.Single-stranded antisense si RNAs guide target RNA cleavage in RNAi.Cell,2002,110(5):563-574
[18]Mcmanus M T,Sharp P A.Gene silencing in mammals by small interfering RNAs.Nature Reviews Genetics,2002,3(10):737-747
[19]Lee Y,Ahn C,Han J,et al.The nuclear RNase III Drosha initiates micro RNA processing.Nature,2003,425(6956):415-419.
[20]Kim V N.Micro RNA biogenesis:coordinated cropping and dicing.Nat Rev Mol Cell Biol,2005,6(5):376-385
[21]Meister G,Tuschl T.Mechanisms of gene silencing by doublestranded RNA.Nature,2004,431(7006):343-349
[22]Lund E,Guttinger S,Calado A,et al.Nuclear export of micro RNAprecursors.Science,2004,303(5654):95-98
[23]Bohnsack M T,Czaplinski K,Gorlich D.Exportin 5 is a Ran GTP-dependent ds RNA-binding protein that mediates nuclear export of pre-mi RNAs.RNA,2004,10(2):185-191
[24]Yi R,Qin Y,Macara I G,et al.Exportin-5 mediates the nuclear export of pre-micro RNAs and short hairpin RNAs.Genes&Development,2003,17(24):3011-3016
[25]Rana T M.Illuminating the silence:understanding the structure and function of small RNAs.Nat Rev Mol Cell Biol,2007,8(1):23-36
[26]Rupaimoole R,Slack F J.Micro RNA therapeutics:towards a new era for the management of cancer and other diseases.Nat Rev Drug Discov,2017,16(3):203-222
[27]Garba A O,Mousa S A.Bevasiranib for the treatment of wet,agerelated macular degeneration.Ophthalmol Eye Dis,2010,2:75-83
[28]Kleinman M E,Yamada K,Takeda A,et al.Sequence-and targetindependent angiogenesis suppression by si RNA via TLR3.Nature,2008,452(7187):591-597
[29]Robbins M,Judge A,Maclachlan I.si RNA and innate immunity.Oligonucleotides,2009,19(2):89-102
[30]Whitehead K A,Langer R,Anderson D G.Knocking down barriers:advances in si RNA delivery.Nat Rev Drug Discov,2009,8(2):129-138
[31]Krieg A M.Is RNAi dead?Mol Ther,2011,19(6):1001-1002
[32]Davis M E,Zuckerman J E,Choi C H,et al.Evidence of RNAi in humans from systemically administered si RNA via targeted nanoparticles.Nature,2010,464(7291):1067-1070
[33]Coelho T,Adams D,Silva A,et al.Safety and efficacy of RNAi therapy for transthyretin amyloidosis.N Engl J Med,2013,369(9):819-829
[34]Nair J K,Willoughby J L,Chan A,et al.Multivalent N-acetylgalactosamine-conjugated si RNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing.J Am Chem Soc,2014,136(49):16958-16961
[35]Foster D J,Brown C R,Shaikh S,et al.Advanced si RNA designs further improve in vivo performance of Gal NAc-si RNAconjugates.Mol Ther,2018,26(3):708-717
[36]Hayden E C.RNA interference rebooted.Nature,2014,508(7497):443
[37]Wu S Y,Lopez-Berestein G,Calin G A,et al.RNAi therapies:drugging the undruggable.Sci Transl Med,2014,6(240):240ps247
[38]Lieberman J,Sharp P A.Harnessing RNA interference for therapy the silent treatment.Jama-Journal of the American Medical Association,2015,313(12):1207-1208
[39]Garber K.Alnylam terminates revusiran program,stock plunges.Nature Biotechnology,2016,34(12):1213-1214
[40]Arrowhead.Arrowhead Pharmaceuticals Focuses Resources on Subcutaneous and Extra-Hepatic RNAi Therapeutics.http://ir.arrowheadpharma.com/static-files/c0ce7c76-51a9-41a6-9a5d-4cc8d6a94dc8.2016,1-2.
[41]Mirna.Mirna Therapeutics Halts Phase 1 Clinical Study of MRX34.https://www.businesswire.com/news/home/20160920006814/en/Mirna-Therapeutics-Halts-Phase-1-Clinical-Study.2016,1-2.
[42]Jayaraman M,Ansell S M,Mui B L,et al.Maximizing the potency of si RNA lipid nanoparticles for hepatic gene silencing in vivo.Angew Chem Int Ed Engl,2012,51(34):8529-8533
[43]Akinc A,Querbes W,De S,et al.Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.Mol Ther,2010,18(7):1357-1364
[44]Akinc A,Zumbuehl A,Goldberg M,et al.A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.Nat Biotechnol,2008,26(5):561-569
[45]Semple S C,Akinc A,Chen J,et al.Rational design of cationic lipids for si RNA delivery.Nat Biotechnol,2010,28(2):172-176
[46]Dong Y,Love K T,Dorkin J R,et al.Lipopeptide nanoparticles for potent and selective si RNA delivery in rodents and nonhuman primates.Proc Natl Acad Sci U S A,2014,111(11):3955-3960
[47]Morrissey D V,Lockridge J A,Shaw L,et al.Potent and persistent in vivo anti-HBV activity of chemically modified si RNAs.Nat Biotechnol,2005,23(8):1002-1007
[48]Huang Y.Preclinical and clinical advances of Gal NAc-decorated nucleic acid therapeutics.Mol Ther Nucleic Acids,2017,6:116-132
[49]Huang Y Y,Liang Z C.Asialoglycoprotein receptor and its application in liver-targeted drug delivery.Prog Biochem Biophys,2015,42(6):501-510
[50]Janas M M,Schlegel M K,Harbison C E,et al.Selection of Gal NAc-conjugated si RNAs with limited off-target-driven rat hepatotoxicity.Nat Commun,2018,9(1):723
[51]Arrowhead.Compositions and Methods for Inhibiting Gene Expression of Factor XII:World Intellectual Property Organization,WO2016149331:1-137.2016-09-22
[52]Khvorova A,Watts J K.The chemical evolution of oligonucleotide therapies of clinical utility.Nat Biotechnol,2017,35(3):238-248
[53]Craig K,Abrams M,Amiji M.Recent preclinical and clinical advances in oligonucleotide conjugates.Expert Opin Drug Deliv,2018,15(6):629-640
[54]Chen C,Yang Z,Tang X.Chemical modifications of nucleic acid drugs and their delivery systems for gene-based therapy.Med Res Rev,2018,38(3):829-869
[55]Hudson A J,Lee W,Porter J,et al.Stability of antisense oligonucleotides during incubation with a mixture of isolated lysosomal enzymes.International Journal of Pharmaceutics,1996,133(1-2):257-263
[56]Alnylam.Phase 1 study of ALN-TTRsc02,a subcutaneously administered investigational RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis.http://www.alnylam.com/wp-content/uploads/2018/03/10.-TTR-SCO2_FINAL.pdf.2018,1-1
[57]Janas M M,Harbison C E,Perry V K,et al.The nonclinical safety profile of Gal NAc-conjugated RNAi therapeutics in subacute studies.Toxicol Pathol,2018,46(7):735-745
[58]Zlatev I,Castoreno A,Brown C R,et al.Reversal of si RNA-mediated gene silencing in vivo.Nat Biotechnol,2018,36(6):509-511
[59]Alnylam.Alnylam R&D Day 2018.https://www.alnylam.com/wp-content/uploads/2018/12/RD_Day2018_FINAL_Capella.pdf.2018,1-236
[60]Arrowhead.Investor and Analyst R&D Day 2018.http://ir.arrowheadpharma.com/static-files/b671502e-ce6a-4346-9b83-00a366789816.2018,1-122