提示: 手机请竖屏浏览!

使用寡核苷酸在RNA水平治疗疾病
Treating Disease at the RNA Level with Oligonucleotides


Arthur A. Levin ... 其他 • 2019.01.03

现在可以使用作用于RNA的药物治疗像脊髓性肌萎缩和高脂血症这样迥异的疾病。一类新的药物(寡核苷酸)利用沃森和克里克的碱基配对规则来靶向与疾病相关的RNA。利用人类基因组测序信息,有可能仅根据基因组信息设计治疗性寡核苷酸,治疗性寡核苷酸将改变任何蛋白质的表达,甚至是采用包括小分子药物在内的传统方法难以改变的蛋白质表达。

虽然早在1978年就已经描述了使用合成寡核苷酸来调节RNA功能的设想1,但是以美国食品药品管理局(FDA)批准的药物这一形式实现上述设想,需要在基因组学、化学、药理学和药物递送方面取得进展。此外,用于以下各种不同用途的数十种寡核苷酸正处于临床试验阶段:治疗血友病、淀粉样变性和高脂血症以及止血2-9。本文描述了以截然不同的方式靶向RNA的四种寡核苷酸,以及治疗性寡核苷酸领域的新方向。





作者信息

Arthur A. Levin, Ph.D.
From Research and Development, Avidity Biosciences, La Jolla, CA. Address reprint requests to Dr. Levin at art.levin@aviditybio.com.

 

参考文献

1. Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 1978;75:280-284.

2. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-1440.

3. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369:819-829.

4. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51.

5. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377:1723-1732.

6. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377:222-232.

7. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438-447.

8. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016;388:2239-2253.

9. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015;372:232-240.

10. Nobile C, Galvagni F, Marchi J, Roberts R, Vitiello L. Genomic organization of the human dystrophin gene across the major deletion hot spot and the 3′ region. Genomics 1995;28:97-100.

11. Cieply B, Carstens RP. Functional roles of alternative splicing factors in human disease. Wiley Interdiscip Rev RNA 2015;6:311-326.

12. Tazi J, Bakkour N, Stamm S. Alternative splicing and disease. Biochim Biophys Acta 2009;1792:14-26.

13. Koenig M, Beggs AH, Moyer M, et al. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 1989;45:498-506.

14. Aartsma-Rus A, Straub V, Hemmings R, et al. Development of exon skipping therapies for Duchenne muscular dystrophy: a critical review and a perspective on the outstanding issues. Nucleic Acid Ther 2017;27:251-259.

15. Eteplirsen briefing document NDA 206488. Cambridge, MA: Sarepta Therapeutics, January 22, 2016 (https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm481912.pdf).

16. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. Press release of the Food and Drug Administration, September 19, 2016 (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm).

17. Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis 1996;3:97-110.

18. Lim SR, Hertel KJ. Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J Biol Chem 2001;276:45476-45483.

19. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009;85:408-413.

20. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 2007;5(4):e73-e73.

21. Rigo F, Chun SJ, Norris DA, et al. Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther 2014;350:46-55.

22. Rigo F, Hua Y, Krainer AR, Bennett CF. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol 2012;199:21-25.

23. FDA approves first drug for spinal muscular atrophy. Press release of the Food and Drug Administration, December 23, 2016 (https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm).

24. Akdim F, Stroes ESG, Sijbrands EJG, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol 2010;55:1611-1618.

25. Kastelein JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 2006;114:1729-1735.

26. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:998-1006.

27. Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol 2016;10:1011-1021.

28. Khvorova A. Oligonucleotide therapeutics — a new class of cholesterol-lowering drugs. N Engl J Med 2017;376:4-7.

29. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144-2153.

30. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379:22-31.

31. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379:11-21.

32. Vickers TA, Wyatt JR, Freier SM. Effects of RNA secondary structure on cellular antisense activity. Nucleic Acids Res 2000;28:1340-1347.

33. Gredell JA, Berger AK, Walton SP. Impact of target mRNA structure on siRNA silencing efficiency: a large-scale study. Biotechnol Bioeng 2008;100:744-755.

34. Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides 2008;18:305-319.

35. Krieg AM, Wu T, Weeratna R, et al. Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci U S A 1998;95:12631-12636.

36. Hartmann G, Weeratna RD, Ballas ZK, et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 2000;164:1617-1624.

37. Judge A, MacLachlan I. Overcoming the innate immune response to small interfering RNA. Hum Gene Ther 2008;19:111-124.

38. Judge AD, Bola G, Lee AC, MacLachlan I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 2006;13:494-505.

39. van Meer L, Moerland M, Gallagher J, et al. Injection site reactions after subcutaneous oligonucleotide therapy. Br J Clin Pharmacol 2016;82:340-351.

40. Advisory Committee briefing materials: available for public release — drisapersen briefing document NDA 206031. Novato, CA: Biomarin, November 24, 2015 ((https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm).).

Google Scholar

41. Nemunaitis J, Holmlund JT, Kraynak M, et al. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 1999;17:3586-3595.

42. Chi KN, Siu LL, Hirte H, et al. A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res 2008;14:833-839.

43. Pepini T, Pulichino A-M, Carsillo T, et al. Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design. J Immunol 2017;198:4012-4024.

44. Geall AJ, Verma A, Otten GR, et al. Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci U S A 2012;109:14604-14609.

45. FDA briefing document for the Peripheral and Central Nervous System Drugs Advisory Committee: drisapersen. November 24, 2015 ((https://wayback.archive-it.org/7993/20170405224801/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM473737.pdf).).

46. Crooke ST, Baker BF, Pham NC, et al. The effects of 2′-O -methoxyethyl oligonucleotides on renal function in humans. Nucleic Acid Ther 2018;28:10-22.

47. van Poelgeest EP, Swart RM, Betjes MG, et al. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am J Kidney Dis 2013;62:796-800.

48. van Poelgeest EP, Hodges MR, Moerland M, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol 2015;80:1350-1361.

49. Crooke ST, Baker BF, Witztum JL, et al. The effects of 2′-O-methoxyethyl containing antisense oligonucleotides on platelets in human clinical trials. Nucleic Acid Ther 2017;27:121-129.

50. Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol Ther Nucleic Acids 2017;6:116-132.

51. Sugo T, Terada M, Oikawa T, et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 2016;237:1-13.

52. Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010;464:1067-1070.

53. Alexander M, Hu R, Runtsch MC, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun 2015;6:7321-7321.

54. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2011;2:282-282.

55. Okoye IS, Coomes SM, Pelly VS, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity 2014;41:89-103.

56. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011;29:341-345.

57. Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017;546:498-503.

58. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-659.

59. Ferguson SW, Nguyen J. Exosomes as therapeutics: the implications of molecular composition and exosomal heterogeneity. J Control Release 2016;228:179-190.

60. Hecker M, Wagner AH. Transcription factor decoy technology: a therapeutic update. Biochem Pharmacol 2017;144:29-34.

61. Portnoy V, Lin SHS, Li KH, et al. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Res 2016;26:320-335.

62. Li L-C, ed. RNA activation. Singapore: Springer, 2017.

63. Corey DR. RNA-mediated gene activation: identifying a candidate RNA for preclinical development.Adv Exp Med Biol 2017;983:161-171.

64. Voutila J, Reebye V, Roberts TC, et al. Development and mechanism of small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for liver cancer. Mol Ther 2017;25:2705-2714.

65. Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 2016;17:83-96.

66. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 2010;79:321-349.

67. Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJC. Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. Proc Natl Acad Sci U S A 2013;110:18285-18290.

68. Jiang F, Doudna JA. CRISPR-Cas9 structures and mechanisms. Annu Rev Biophys 2017;46:505-529.

69. Cox DBT, Gootenberg JS, Abudayyeh OO, et al. RNA editing with CRISPR-Cas13. Science 2017;358:1019-1027.

70. Wang M, Glass ZA, Xu Q. Non-viral delivery of genome-editing nucleases for gene therapy. Gene Ther 2017;24:144-150.

71. Liu C, Zhang L, Liu H, Cheng K. Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications. J Control Release 2017;266:17-26.

72. Charlesworth CT, Deshpande PS, Dever DP, et al. Identification of pre-existing adaptive immunity to Cas9 proteins in humans. bioRxiv. January 5, 2018.

73. Li D, Qiu Z, Shao Y, et al. Heritable gene targeting in the mouse and rat using a CRISPR-Cas system. Nat Biotechnol 2013;31:681-683.

74. Bernards R, Filipowicz W, Livingston DM, Mihich E. Twenty-second annual Pezcoller Symposium: RNA biology and cancer. Cancer Res 2010;70:10034-10037.

75. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010;11:597-610.

76. Janssen HLA, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013;368:1685-1694.

77. van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A 2008;105:13027-13032.

78. Zhang G-Y, Wu L-C, Liao T, et al. A novel regulatory function for miR-29a in keloid fibrogenesis. Clin Exp Dermatol 2016;41:341-345.

79. Harmanci D, Erkan EP, Kocak A, Akdogan GG. Role of the microRNA-29 family in fibrotic skin diseases. Biomed Rep 2017;6:599-604.

80. Roderburg C, Urban G-W, Bettermann K, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011;53:209-218.

81. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet 2009;10:155-159.

服务条款 | 隐私政策 | 联系我们