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Messenger RNA as a Novel Therapeutic Approach

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RNA Therapeutics

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 27))

Abstract

The concept of mRNA as a therapeutic platform has historically been ignored owing to challenges in oligonucleotide delivery and, maybe more importantly, the perceived shortcomings of mRNA with regard to stability and immunogenicity. Advances in several areas have recently prompted a reexamination of such dogma. Significant improvements in oligonucleotide delivery have been realized over the past decade and their application to mRNA has enabled a more rapid path toward clinical development of this new modality. Similarly, recent discoveries in mRNA chemistry further enhance the attractiveness of this platform by attenuating innate immune activation and maximizing protein expression. With these advances, mRNA is positioned to become an important new therapeutic modality.

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References

  1. http://labiotech.eu/ultimate-review-how-could-mrna-overtake-all-other-biologicals-in-medicine/

  2. Zangi L, Lui KO, von Gise A et al (2013) Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 31:898–907

    Article  CAS  Google Scholar 

  3. Karikó K, Muramatsu H, Keller JM et al (2012) Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol Ther 20:948–953

    Article  Google Scholar 

  4. Phua KKL, Leong KW, Nair SK (2013) Transfection efficiency and transgene expression kinetics of mRNA delivered in naked and nanoparticle format. J Control Release 201:41–48

    Google Scholar 

  5. Kormann MSD, Hasenpusch G, Aneja MK et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29:154–157

    Article  CAS  Google Scholar 

  6. Wang Y, H-h S, Yang Y et al (2013) Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. Mol Ther 21:358–367

    Article  CAS  Google Scholar 

  7. Kranz LM, Diken M, Haas H et al (2016) Systemic delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534:396–401

    Article  Google Scholar 

  8. Yin H, Kanasty RL, Eltoukhy AA et al (2014) Non-viral vectors for gene based therapies. Nat Rev 15:541–555

    Article  CAS  Google Scholar 

  9. Bobbin ML, Rossi JJ (2016) RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu Rev Pharmacol Toxicol 56:103–122

    Article  CAS  Google Scholar 

  10. Hope MJ (2014) Enhancing siRNA delivery by employing lipid nanoparticles. Ther Deliv 5:663–673

    Article  CAS  Google Scholar 

  11. Akinc A, Querbes W, De S et al (2010) Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther 18:1357–1364

    Article  CAS  Google Scholar 

  12. Geall AJ, Verma A, Otten GR et al (2012) Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci 109:14604–14609

    Article  CAS  Google Scholar 

  13. Hekele A, Bertholet S, Archer J et al (2013) Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice. Emerg Microb Infect 2:e52

    Article  Google Scholar 

  14. Pardi N, Tuyishime S, Muranatsu H et al (2015) Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 217:345–351

    Article  CAS  Google Scholar 

  15. Thess A, Grund S, Mui BL et al (2015) Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 23:1456–1464

    Article  CAS  Google Scholar 

  16. Nabhan JF, Wood KM, Rao VP (2016) Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia. Sci Rep 6:1–10

    Article  Google Scholar 

  17. Love KT, Mahon KP, Levins CG et al (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci 107:1864–1869

    Article  CAS  Google Scholar 

  18. Kauffman KJ, Dorkin JR, Yang JH et al (2015) Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Lett 51:7300–7306

    Article  Google Scholar 

  19. DeRosa F, Guild B, Karve S et al (2016) Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA depot system. Gene Ther 23(10):699–707

    Article  CAS  Google Scholar 

  20. Dong Y, Love KT, Dorkin JR et al (2014) Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc Natl Acad Sci 111:3955–3960

    Article  CAS  Google Scholar 

  21. Fenton OS, Kauffman KJ, McClellean RL et al (2016) Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery. Adv Mater 28:2939–2943

    Article  CAS  Google Scholar 

  22. Li B, Luo B, Deng B (2015) An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett 15:8099–8107

    Article  CAS  Google Scholar 

  23. Li B, Luo X, Deng B (2016) Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Sci Rep 6:22137

    Article  CAS  Google Scholar 

  24. Jarzębińska A, Pasewald T, Lambrecht J et al (2016) A single methylene group in oligoalkylamine-based cationic polymers and lipids promotes enhanced mRNA delivery. Angew Chem Int Ed 55:9591–9595

    Article  Google Scholar 

  25. Lächelt U, Wagner E (2015) Nucleic acid therapeutics using polyplexes: a journey of 50 years (and beyond). Chem Rev 115:11043–11078

    Article  Google Scholar 

  26. Uchida H, Itaka K, Nomoto T et al (2014) Modulated protonation of side chain aminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection. J Am Chem Soc 136:12396–12405

    Article  CAS  Google Scholar 

  27. Uchida S, Kinoh H, Ishii T et al (2016) Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety. Biomaterials 82:221–228

    Article  CAS  Google Scholar 

  28. Dong Y, Dorkin JR, Wang W et al (2016) Poly(glycoamidoaine) brushes formulated nanomaterials for systemic siRNA and mRNA delivery in vivo. Nano Lett 16:842–848

    Article  CAS  Google Scholar 

  29. Heartlein M, Anderson D, Dong Y, DeRosa F (2015) Lipid formulations for delivery of messenger RNA. WO 2015061467 A1

    Google Scholar 

  30. Heyes J, Palmer LR, Reid SP et al (2015) Compositions and methods for delivering messenger RNA. WO 2015011633 A1

    Google Scholar 

  31. Byers C, Caplan SL, Gamber GG et al (2015) Leptin mRNA compositions and formulations. WO 2015095351 A1

    Google Scholar 

  32. Almarsson O, Lawlor C (2016) Lipid nanoparticle mRNA compositions. WO 2016118725 A1

    Google Scholar 

  33. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR et al (2010) Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 6:146–156

    Article  CAS  Google Scholar 

  34. Picard-Jean F, Tremblay-Létourneau M, Serra E et al (2013) RNA 5′-end maturation: a crucial step in the replication of viral genomes. In: Romanowski V (ed) Current issues in molecular virology-viral genetics and biotechnological applications. http://www.intechopen.com/books/current-issues-in-molecular-virology-viral-genetics-and-biotechnological-applications/rna-5-end-maturation-a-crucial-step-in-the-replication-of-viral-genomes

  35. Kato H, Takeuchi O, Mikamo-Satoh E et al (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610

    Article  CAS  Google Scholar 

  36. Leung DW, Amarasinghe GK (2016) When your cap matters: structural insights into self vs non-self recognition of 5′ RNA by immunomodulatory host proteins. Curr Opin Struct Biol 36:133–141

    Article  CAS  Google Scholar 

  37. Vladimer GI, Górna MW, Superti-Furga G (2014) IFITs: emerging roles as key anti-viral proteins. Front Immunol 5(9):1–9

    CAS  Google Scholar 

  38. Milligan JF, Groebe DR, Witherell GW, Uhlenbeck OC (1987) Oligoribonucleotide synthesis using T7 RNA polymerase and synthetic DNA templates. Nucleic Acids Res 15:8783–8798

    Article  CAS  Google Scholar 

  39. Triana-Alonso FJ, Dabrowski M, Wadzack J, Nierhaus KH (1995) Self-coded 3′-extension of run-off transcripts produces aberrant products during in vitro transcription with T7 RNA polymerase. J Biol Chem 270:6298–6307

    Article  CAS  Google Scholar 

  40. Nacheva GA, Berzal-Herranz A (2003) Preventing nondesired RNA-primed RNA extension catalyzed by T7 RNA polymerase. Eur J Biochem 270:1458–1465

    Article  CAS  Google Scholar 

  41. Arnaud-Barbe N, Cheynet-Sauvion V, Oriol G et al (1998) Transcription of RNA templates by T7 RNA polymerase. Nucleic Acids Res 26:3550–3554

    Article  CAS  Google Scholar 

  42. Karikó K, Muramatsu H, Ludwig J, Weissman D (2011) Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-coding mRNA. Nucleic Acids Res 39:e142

    Article  Google Scholar 

  43. Karikó K, Buckstein M, Ni H, Weissman D (2005) Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23:165–175

    Article  Google Scholar 

  44. Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, Weissman D (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 16:1833–1840

    Article  Google Scholar 

  45. Nallagatla SR, Bevilacqua PC (2008) Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner. RNA 14:1201–1213

    Article  CAS  Google Scholar 

  46. Anderson BR, Muramatsu H, Nallagatla SR, Bevilacqua PC, Sansing LH, Weissman D, Karikó K (2010) Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 38:5884–5892

    Article  CAS  Google Scholar 

  47. Warren L, Manos PD, Ahfeldt T, Loh Y-H, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaegar TM, Rossi DJ (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–630

    Article  CAS  Google Scholar 

  48. Schrum, JP, Afeyan NB, Seiczkiewicz GJ, Bancel S, de Fougerolles A, Elbashir S (2012) US 20120251618 Delivery and formulation of engineered nucleic acids

    Google Scholar 

  49. de Fougerolles A, Roy A, Schrum JP, Siddiqi S, Hatala P, Bancel S (2013) US 20130115272 Modified nucleosides, nucleotides, and nucleic acids, and uses thereof

    Google Scholar 

  50. Pardi N, Tuyishme S, Muramatsu H et al (2015) Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Controlled Release 217:345–351

    Article  CAS  Google Scholar 

  51. Andries O, McCafferty S, De Smedt SC et al (2015) N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Controlled Release 217:337–344

    Article  CAS  Google Scholar 

  52. Li B, Luo X, Dong Y (2016) Effects of chemically modified messenger RNA on protein expression. Bioconjug Chem 27:849–853

    Article  CAS  Google Scholar 

  53. Presnyak V, Alhusaini N, Chen YH et al (2015) Codon optimality is a major determinant of mRNA stability. Cell 160:1111–1124

    Article  CAS  Google Scholar 

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Correspondence to Matthew G. Stanton .

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Stanton, M.G., Murphy-Benenato, K.E. (2017). Messenger RNA as a Novel Therapeutic Approach. In: Garner, A. (eds) RNA Therapeutics. Topics in Medicinal Chemistry, vol 27. Springer, Cham. https://doi.org/10.1007/7355_2016_30

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