Tapping the RNA world for therapeutics

Abstract

A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

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Fig. 1: Antisense mechanisms of RNA-based drugs.

Debbie Maizels/Springer Nature

Fig. 2: Additional RNA-based drug mechanisms.

Debbie Maizels/Springer Nature

Fig. 3: RNA-based drug delivery strategies.

Debbie Maizels/Springer Nature

References

  1. 1.

    Cech, T. R. & Steitz, J. A. The noncoding RNA revolution—trashing old rules to forge new ones. Cell 157, 77–94 (2014).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Deveson, I. W., Hardwick, S. A., Mercer, T. R. & Mattick, J. S. The dimensions, dynamics, and relevance of the mammalian noncoding transcriptome. Trends Genet. 33, 464–478 (2017).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Schonrock, N., Jonkhout, N. & Mattick, J. S. Seq and you will find. Curr. Gene Ther. 16, 220–229 (2016).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Brockdorff, N. et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Brown, C. J. et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542 (1992).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Ebert, M. S. & Sharp, P. A. Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nat. Struct. Mol. Biol. 17, 1169–1174 (2010).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Watanabe, T. & Lin, H. Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs. Mol. Cell 56, 18–27 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Holoch, D. & Moazed, D. RNA-mediated epigenetic regulation of gene expression. Nat. Rev. Genet. 16, 71–84 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Iwasaki, Y. W., Siomi, M. C. & Siomi, H. PIWI-interacting RNA: its biogenesis and functions. Annu. Rev. Biochem. 84, 405–433 (2015).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Janowski, B. A. et al. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. 3, 166–173 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Li, L. C. et al. Small dsRNAs induce transcriptional activation in human cells. Proc. Natl Acad. Sci. USA 103, 17337–17342 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Breaker, R. R. Riboswitches and the RNA world. Cold Spring Harb. Perspect. Biol. 4, a003566 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Gelinas, A. D., Davies, D. R. & Janjic, N. Embracing proteins: structural themes in aptamer–protein complexes. Curr. Opin. Struct. Biol. 36, 122–132 (2016).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Sharp, P. A. On the origin of RNA splicing and introns. Cell 42, 397–400 (1985).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Gilbert, W. Origin of life: the RNA world. Nature 319, 618 (1986).

    Article  Google Scholar 

  23. 23.

    Holbrook, S. R. RNA structure: the long and the short of it. Curr. Opin. Struct. Biol. 15, 302–308 (2005).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Ellington, A. D. & Szostak, J. W. In vitro selection of RNA molecules that bind specific ligands. Nature 346, 818–822 (1990).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Tuerk, C. & Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505–510 (1990).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Serganov, A. & Nudler, E. A decade of riboswitches. Cell 152, 17–24 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Quinn, J. J. & Chang, H. Y. Unique features of long non-coding RNA biogenesis and function. Nat. Rev. Genet. 17, 47–62 (2016).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Chen, K., Zhao, B. S. & He, C. Nucleic acid modifications in regulation of gene expression. Cell Chem. Biol. 23, 74–85 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Kopp, F. & Mendell, J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell 172, 393–407 (2018).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Zamecnik, P. C. & Stephenson, M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc. Natl Acad. Sci. USA 75, 280–284 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Stephenson, M. L. & Zamecnik, P. C. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc. Natl Acad. Sci. USA 75, 285–288 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Dixon, S. J. & Stockwell, B. R. Identifying druggable disease-modifying gene products. Curr. Opin. Chem. Biol. 13, 549–555 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Fauman, E. B., Rai, B. K. & Huang, E. S. Structure-based druggability assessment—identifying suitable targets for small molecule therapeutics. Curr. Opin. Chem. Biol. 15, 463–468 (2011).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Cirak, S. et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378, 595–605 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Gorski, S. A., Vogel, J. & Doudna, J. A. RNA-based recognition and targeting: sowing the seeds of specificity. Nat. Rev. Mol. Cell Biol. 18, 215–228 (2017).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Bennett, C. F., Baker, B. F., Pham, N., Swayze, E. & Geary, R. S. Pharmacology of antisense drugs. Annu. Rev. Pharmacol. Toxicol. 57, 81–105 (2017).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Crooke, S. T. Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Ther. 27, 70–77 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Crooke, S. T., Wang, S., Vickers, T. A., Shen, W. & Liang, X. H. Cellular uptake and trafficking of antisense oligonucleotides. Nat. Biotechnol. 35, 230–237 (2017).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Khvorova, A. & Watts, J. K. The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol. 35, 238–248 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Raal, F. J. 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 375, 998–1006 (2010).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Liang, X. H. et al. Translation efficiency of mRNAs is increased by antisense oligonucleotides targeting upstream open reading frames. Nat. Biotechnol. 34, 875–880 (2016).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Krützfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Lum, L. et al. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039–2045 (2003).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Caplen, N. J., Fleenor, J., Fire, A. & Morgan, R. A. dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference. Gene 252, 95–105 (2000).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Fraser, A. G. et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Boutros, M. et al. Genome-wide RNAi analysis of growth and viability in Drosophila cells. Science 303, 832–835 (2004).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Silva, J. M. et al. Profiling essential genes in human mammary cells by multiplex RNAi screening. Science 319, 617–620 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Schlabach, M. R. et al. Cancer proliferation gene discovery through functional genomics. Science 319, 620–624 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Paddison, P. J. et al. A resource for large-scale RNA-interference-based screens in mammals. Nature 428, 427–431 (2004).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Novina, C. D. et al. siRNA-directed inhibition of HIV-1 infection. Nat. Med. 8, 681–686 (2002).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Jacque, J. M., Triques, K. & Stevenson, M. Modulation of HIV-1 replication by RNA interference. Nature 418, 435–438 (2002).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Martínez, M. A. et al. Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. AIDS 16, 2385–2390 (2002).

    PubMed  Article  Google Scholar 

  61. 61.

    Park, W. S. et al. Prevention of HIV-1 infection in human peripheral blood mononuclear cells by specific RNA interference. Nucleic Acids Res. 30, 4830–4835 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Surabhi, R. M. & Gaynor, R. B. RNA interference directed against viral and cellular targets inhibits human immunodeficiency virus type 1 replication. J. Virol. 76, 12963–12973 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med. 9, 347–351 (2003).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002–1007 (2005).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Judge, A. D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat. Biotechnol. 23, 457–462 (2005).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Jackson, A. L. et al. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12, 1197–1205 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Rajeev, K. G. et al. Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. ChemBioChem 16, 903–908 (2015).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Matsuda, S. et al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chem. Biol. 10, 1181–1187 (2015).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Biessen, E. A. et al. Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes. Bioconjug. Chem. 13, 295–302 (2002).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Zimmermann, T. S. et al. Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate. Mol. Ther. 25, 71–78 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Garber, K. Worth the RISC? Nat. Biotechnol. 35, 198–202 (2017).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Pasi, K. J. et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N. Engl. J. Med. 377, 819–828 (2017).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Yasuda, M. et al. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc. Natl Acad. Sci. USA 111, 7777–7782 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Dutta, C. et al. Inhibition of glycolate oxidase with Dicer-substrate siRNA reduces calcium oxalate deposition in a mouse model of primary hyperoxaluria type 1. Mol. Ther. 24, 770–778 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Liebow, A. et al. An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J. Am. Soc. Nephrol. 28, 494–503 (2017).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Huang, Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol. Ther. Nucleic Acids 6, 116–132 (2017).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Prakash, T. P. et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42, 8796–8807 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Tanowitz, M. et al. Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes. Nucleic Acids Res. 45, 12388–12400 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Dassie, J. P. et al. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat. Biotechnol. 27, 839–846 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    McNamara, J. O. II et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat. Biotechnol. 24, 1005–1015 (2006).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Zhou, J. & Rossi, J. Aptamers as targeted therapeutics: current potential and challenges. Nat. Rev. Drug Discov. 16, 181–202 (2017).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat. Biotechnol. 27, 925–932 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Peer, D., Zhu, P., Carman, C. V., Lieberman, J. & Shimaoka, M. Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc. Natl Acad. Sci. USA 104, 4095–4100 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Song, E. et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 23, 709–717 (2005).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Ramishetti, S., Landesman-Milo, D. & Peer, D. Advances in RNAi therapeutic delivery to leukocytes using lipid nanoparticles. J. Drug Target. 24, 780–786 (2016).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Weinstein, S. et al. Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies. Proc. Natl Acad. Sci. USA 113, E16–E22 (2016).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Nikan, M. et al. Docosahexaenoic acid conjugation enhances distribution and safety of siRNA upon local administration in mouse brain. Mol. Ther. Nucleic Acids 5, e344 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Kedmi, R. et al. A modular platform for targeted RNAi therapeutics. Nat. Nanotechnol. 13, 214–219 (2018).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Gilboa-Geffen, A. et al. Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells. Mol. Cancer Ther. 14, 2279–2291 (2015).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Esposito, C. L. et al. Multifunctional aptamer-miRNA conjugates for targeted cancer therapy. Mol. Ther. 22, 1151–1163 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Sasaki, S. & Guo, S. Nucleic acid therapies for cystic fibrosis. Nucleic Acid Ther. 28, 1–9 (2018).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Yin, H. et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat. Biotechnol. 32, 551–553 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Nelson, C. E. et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Tabebordbar, M. et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Komor, A. C., Badran, A. H. & Liu, D. R. CRISPR-based technologies for the manipulation of eukaryotic genomes. Cell 168, 20–36 (2017).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Fellmann, C., Gowen, B. G., Lin, P. C., Doudna, J. A. & Corn, J. E. Cornerstones of CRISPR–Cas in drug discovery and therapy. Nat. Rev. Drug Discov. 16, 89–100 (2017).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Dowdy, S. F. Overcoming cellular barriers for RNA therapeutics. Nat. Biotechnol. 35, 222–229 (2017).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Wang, H. X. et al. CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery. Chem. Rev. 117, 9874–9906 (2017).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Graham, M. J. et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48, 763–767 (2007).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Karatasakis, A. et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J. Am. Heart Assoc. 6, e006910 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Benson, M. D., Dasgupta, N. R., Rissing, S. M., Smith, J. & Feigenbaum, H. Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid 24, 219–225 (2017).

    PubMed  Google Scholar 

  108. 108.

    Deltcheva, E. et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471, 602–607 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Marraffini, L. A. & Sontheimer, E. J. CRISPR interference limits horizontal gene transfer in staphylococci by targeting DNA. Science 322, 1843–1845 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Barrangou, R. The roles of CRISPR–Cas systems in adaptive immunity and beyond. Curr. Opin. Immunol. 32, 36–41 (2015).

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007).

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Cornu, T. I., Mussolino, C. & Cathomen, T. Refining strategies to translate genome editing to the clinic. Nat. Med. 23, 415–423 (2017).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Russell, S. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Weissman, D. et al. HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response. J. Immunol. 165, 4710–4717 (2000).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Weissman, D. & Karikó, K. mRNA: fulfilling the promise of gene therapy. Mol. Ther. 3, 1416–1417 (2015).

    Article  CAS  Google Scholar 

  120. 120.

    Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. https://dx.doi.org/10.1038/nrd.2017.243 (2018).

  121. 121.

    Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  122. 122.

    Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Dassie, J. P. & Giangrande, P. H. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther. Deliv. 4, 1527–1546 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Keefe, A. D., Pai, S. & Ellington, A. Aptamers as therapeutics. Nat. Rev. Drug Discov. 9, 537–550 (2010).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Gold, L., Walker, J. J., Wilcox, S. K. & Williams, S. Advances in human proteomics at high scale with the SOMAscan proteomics platform. N. Biotechnol. 29, 543–549 (2012).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Lollo, B., Steele, F. & Gold, L. Beyond antibodies: new affinity reagents to unlock the proteome. Proteomics 14, 638–644 (2014).

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Lieberman, J. Manipulating the in vivo immune response by targeted gene knockdown. Curr. Opin. Immunol. 35, 63–72 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This work was supported by NIH CA13944.

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Correspondence to Judy Lieberman.

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J.L. is on the Scientific Advisory Board of Alnylam Pharmaceuticals.

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Lieberman, J. Tapping the RNA world for therapeutics. Nat Struct Mol Biol 25, 357–364 (2018). https://doi.org/10.1038/s41594-018-0054-4

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