Concise Review: Application of In Vitro Transcribed Messenger RNA for Cellular Engineering and Reprogramming: Progress and Challenges

Stem Cells

Volumn 35, Issue 1, 2017, Pages 68-79

  Steinle, Heidrun ^a   Behring, Andreas ^a   Schlensak, Christian ^a   Wendel, Hans Peter ^a   Avci Adali, Meltem ^a  

^a UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

Author keywords

Cell engineering; Direct cell conversion; Gene delivery systems in vivo or in vitro; Gene expression; Induced pluripotent stem cells; Reprogramming; Synthetic messenger RNA

Indexed keywords

5 METHYLCYTIDINE; ADENOSINE DEAMINASE; B7 ANTIGEN; CASPASE RECRUITMENT DOMAIN PROTEIN 15; CD19 ANTIGEN; CD86 ANTIGEN; CRYOPYRIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERFERON; INTERFERON INDUCED HELICASE C DOMAIN CONTAINING PROTEIN 1; INTERFERON REGULATORY FACTOR; INTERFERON REGULATORY FACTOR 7; INTERLEUKIN 12; INTERLEUKIN 15; KRUPPEL LIKE FACTOR 4; MESSENGER RNA; MYC PROTEIN; OCTAMER TRANSCRIPTION FACTOR 4; PATTERN RECOGNITION RECEPTOR; PSEUDOURIDINE; RETINOIC ACID INDUCIBLE PROTEIN I; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TRANSCRIPTION FACTOR LIN28; TRANSCRIPTION FACTOR SOX2; UNCLASSIFIED DRUG; VIRUS VECTOR;

CANCER THERAPY; CELL ENGINEERING; CELL TRANSDIFFERENTIATION; CELLS BY BODY ANATOMY; DENDRITIC CELL; GENE EXPRESSION PROFILING; GENETIC DISORDER; GENETIC TRANSCRIPTION; HUMAN; IMMUNE RESPONSE; IN VITRO GENE TRANSFER; IN VITRO STUDY; IN VITRO TRANSCRIBED MESSENGER RNA; IN VIVO STUDY; INDUCED PLURIPOTENT STEM CELL; NONHUMAN; NUCLEAR REPROGRAMMING; PROTEIN EXPRESSION; PROTEIN MODIFICATION; PROTEIN SYNTHESIS; REVIEW; SOMATIC CELL; SURFACE PROPERTY; VACCINATION; ANIMAL; GENETICS; METABOLISM;

ANIMALS; CELL ENGINEERING; CELLULAR REPROGRAMMING; HUMANS; PROTEIN BIOSYNTHESIS; RNA, MESSENGER; TRANSCRIPTION, GENETIC;

EID: 84978794972     PISSN: 10665099     EISSN: 15494918     Source Type: Journal    
DOI: 10.1002/stem.2402     Document Type: Review

References (112)

1. Griesenbach U, Pytel KM Alton EW. Cystic fibrosis gene therapy in the UK and Elsewhere. Hum Gene Ther 2015;26:266–275.
2. Bangel-Ruland N, Tomczak K, Fernandez Fernandez E et al. Cystic fibrosis transmembrane conductance regulator-mRNA delivery: A novel alternative for cystic fibrosis gene therapy. J Gene Med 2013;15:414–426.
3. Kormann MS, Hasenpusch G, Aneja MK et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 2011;29:154–157.
4. Garcia F, Plana M, Climent N et al. Dendritic cell based vaccines for HIV infection: The way ahead. Hum Vaccin Immunother 2013;9:2445–2452.
5. Petsch B, Schnee M, Vogel AB et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza a virus infection. Nat Biotechnol 2012;30:1210–1216.
6. Benteyn D, Anguille S, Van Lint S et al. Design of an optimized Wilms' tumor 1 (WT1) mRNA construct for enhanced WT1 expression and improved immunogenicity in vitro and in vivo. Mol Ther Nucleic Acids 2013;2:e134.
7. Levy O, Zhao W, Mortensen LJ et al. mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation. Blood 2013;122:e23–e32.
8. Takahashi K Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–676.
9. Warren L, Manos PD, Ahfeldt T et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010;7:618–630.
10. Stadtfeld M, Nagaya M, Utikal J et al. Induced pluripotent stem cells generated without viral integration. Science 2008;322:945–949.
11. Woltjen K, Michael IP, Mohseni P et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009;458:766–770.
12. Yu J, Hu K, Smuga-Otto K et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009;324:797–801.
13. Seki T, Yuasa S, Oda M et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 2010;7:11–14.
14. Yoshioka N, Gros E, Li HR et al. Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell 2013;13:246–254.
15. Rao MS, Malik N. Assessing iPSC reprogramming methods for their suitability in translational Medicine. J Cell Biochem 2012;113:3061–3068.
16. Steichen C, Luce E, Maluenda J et al. Messenger RNA versus retrovirus-based induced pluripotent stem cell reprogramming strategies: Analysis of genomic integrity. Stem Cells Transl Med 2014;3:686–691.
17. Mallon BS, Hamilton RS, Kozhich OA et al. Comparison of the molecular profiles of human embryonic and induced pluripotent stem cells of isogenic origin. Stem Cell Res 2014;12:376–386.
18. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007;448:313–317.
19. Zhao T, Zhang ZN, Rong Z et al. Immunogenicity of induced pluripotent stem cells. Nature 2011;474:212–215.
20. Hu K. All roads lead to induced pluripotent stem cells: The technologies of iPSC generation. Stem Cells Dev 2014;23:1285–1300.
21. Kaji K, Norrby K, Paca A et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009;458:771–775.
22. Yakubov E, Rechavi G, Rozenblatt S et al. Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem Biophys Res Commun 2010;394:189–193.
23. Plews JR, Li J, Jones M et al. Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach. PLoS One 2010;5:e14397.
24. Schlaeger TM, Daheron L, Brickler TR et al. A comparison of non-integrating reprogramming methods. Nat Biotechnol 2015;33:58–63.
25. Zangi L, Lui KO, von Gise A et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 2013;31:898–907.
26. Rettig L, Haen SP, Bittermann AG et al. Particle size and activation threshold: A new dimension of danger signaling. Blood 2010;115:4533–4541.
27. Hu K. Vectorology and factor delivery in induced pluripotent stem cell reprogramming. Stem Cells Dev 2014;23:1301–1315.
28. Bernal JA. RNA-based tools for nuclear reprogramming and lineage-conversion: Towards clinical applications. J Cardiovasc Transl Res 2013;6:956–968.
29. Sahin U, Kariko K, Tureci O. mRNA-based therapeutics–Developing a new class of drugs. Nat Rev Drug Discov 2014;13:759–780.
30. Kariko K, Muramatsu H, Ludwig J et al. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res 2011;39:e142.
31. Kariko K, Muramatsu H, Welsh FA et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 2008;16:1833–1840.
32. Loomis KH, Kirschman JL, Bhosle S et al. Strategies for modulating innate immune activation and protein production of in vitro transcribed mRNAs. J Mater Chem B 2016;4:1619–1632.
33. Hawley-Nelson P, Ciccarone V, Moore ML. Transfection of cultured eukaryotic cells using cationic lipid reagents. Curr Protoc Mol Biol 2008;chapter 9: Unit 9 4.
34. Lorenz C, Fotin-Mleczek M, Roth G et al. Protein expression from exogenous mRNA: Uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. RNA Biol 2011;8:627–636.
35. Bire S, Gosset D, Jegot G et al. Exogenous mRNA delivery and bioavailability in gene transfer mediated by piggyBac transposition. BMC Biotechnol 2013;13:75.
36. Van Tendeloo VF, Ponsaerts P, Berneman ZN. mRNA-based gene transfer as a tool for gene and cell therapy. Curr Opin Mol Ther 2007;9:423–431.
37. Alexopoulou L, Holt AC, Medzhitov R et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001;413:732–738.
38. Kariko K, Ni H, Capodici J et al. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 2004;279:12542–12550.
39. Diebold SS, Kaisho T, Hemmi H et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303:1529–1531.
40. Diebold SS, Massacrier C, Akira S et al. Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 2006;36:3256–3267.
41. Heil F, Hemmi H, Hochrein H et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303:1526–1529.
42. Lorenzi JC, Trombone AP, Rocha CD et al. Intranasal vaccination with messenger RNA as a new approach in gene therapy: Use against tuberculosis. BMC Biotechnol 2010;10:77.
43. Schlee M, Roth A, Hornung V et al. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 2009;31:25–34.
44. Schmidt A, Schwerd T, Hamm W et al. 5′-Triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc Natl Acad Sci U S A 2009;106:12067–12072.
45. Goubau D, Schlee M, Deddouche S et al. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature 2014;514:372–375.
46. Devarkar SC, Wang C, Miller MT et al. Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I. Proc Natl Acad Sci U S A 2016;113:596–601.
47. Schuberth-Wagner C, Ludwig J, Bruder AK et al. A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2′O-methylated self RNA. Immunity 2015;43:41–51.
48. Kato H, Takeuchi O, Mikamo-Satoh E et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 2008;205:1601–1610.
49. Zust R, Cervantes-Barragan L, Habjan M et al. Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol 2011;12:137–143.
50. Pichlmair A, Schulz O, Tan CP et al. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol 2009;83:10761–10769.
51. Kanneganti TD, Body-Malapel M, Amer A et al. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 2006;281:36560–36568.
52. Sabbah A, Chang TH, Harnack R et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol 2009;10:1073–1080.
53. Devoldere J, Dewitte H, De Smedt SC et al. Evading innate immunity in nonviral mRNA delivery: Don't shoot the messenger. Drug Discov Today 2016;21:11–25.
54. Loo YM, Gale M Jr., Immune signaling by RIG-I-like receptors. Immunity 2011;34:680–692.
55. Andries O, De Filette M, De Smedt SC et al. Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells. J Control Release 2013;167:157–166.
56. Nallagatla SR, Bevilacqua PC. Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner. RNA 2008;14:1201–1213.
57. Angel M, Yanik MF. Innate immune suppression enables frequent transfection with RNA encoding reprogramming proteins. PLoS One 2010;5:e11756.
58. Hoerr I, Obst R, Rammensee HG et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol 2000;30:1–7.
59. Kariko K, Buckstein M, Ni H et al. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005;23:165–175.
60. Kallen KJ, Thess A. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Ther Adv Vaccines 2014;2:10–31.
61. Kariko K, Weissman D. Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: Implication for therapeutic RNA development. Curr Opin Drug Discov Dev 2007;10:523–532.
62. Quabius ES, Krupp G. Synthetic mRNAs for manipulating cellular phenotypes: An overview. N Biotechnol 2015;32:229–235.
63. Mahiny AJ, Dewerth A, Mays LE et al. In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency. Nat Biotechnol 2015;33:584–586.
64. Poleganov MA, Eminli S, Beissert T et al. Efficient reprogramming of human fibroblasts and blood-derived endothelial progenitor cells using nonmodified RNA for reprogramming and immune evasion. Hum Gene Ther 2015;26:751–766.
65. Preskey D, Allison TF, Jones M et al. Synthetically modified mRNA for efficient and fast human iPS cell generation and direct transdifferentiation to myoblasts. Biochem Biophys Res Commun 2015;3:743–751.
66. Wang Y, Su HH, Yang Y et al. Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. Mol Ther 2013;21:358–367.
67. Kariko K, Muramatsu H, Keller JM et al. Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol Ther 2012;20:948–953.
68. Andries O, Mc Cafferty S, De Smedt SC et al. N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release 2015;217:337–344.
69. Pardi N, Tuyishime S, Muramatsu H et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 2015;217:345–351.
70. Mays LE, Ammon-Treiber S, Mothes B et al. Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism. J Clin Invest 2013;123:1216–1228.
71. Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A 1989;86:6077–6081.
72. Kozak M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res 1987;15:8125–8148.
73. Mockey M, Goncalves C, Dupuy FP et al. mRNA transfection of dendritic cells: synergistic effect of ARCA mRNA capping with poly(a) chains in cis and in trans for a high protein expression level. Biochem Biophys Res Commun 2006;340:1062–1068.
74. Grudzien-Nogalska E, Kowalska J, Su W et al. Synthetic mRNAs with superior translation and stability properties. Methods Mol Biol 2013;969:55–72.
75. Stepinski J, Waddell C, Stolarski R et al. Synthesis and properties of mRNAs containing the novel “anti-reverse” cap analogs 7-methyl(3′-O-methyl)GpppG and 7-methyl (3′-deoxy)GpppG. RNA 2001;7:1486–1495.
76. Grudzien-Nogalska E, Jemielity J, Kowalska J et al. Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells. RNA 2007;13:1745–1755.
77. Hornung V, Ellegast J, Kim S et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 2006;314:994–997.
78. Pichlmair A, Schulz O, Tan CP et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 2006;314:997–1001.
79. Goldstrohm AC, Wickens M. Multifunctional deadenylase complexes diversify mRNA control. Nat Rev Mol Cell Biol 2008;9:337–344.
80. Drews K, Tavernier G, Demeester J et al. The cytotoxic and immunogenic hurdles associated with non-viral mRNA-mediated reprogramming of human fibroblasts. Biomaterials 2012;33:4059–4068.
81. Rautsi O, Lehmusvaara S, Salonen T et al. Type I interferon response against viral and non-viral gene transfer in human tumor and primary cell lines. J Gene Med 2007;9:122–135.
82. Avci-Adali M, Behring A, Keller T et al. Optimized conditions for successful transfection of human endothelial cells with in vitro synthesized and modified mRNA for induction of protein expression. J Biol Eng 2014;8:8.
83. Schwartz SD, Hubschman JP, Heilwell G et al. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet 2012;379:713–720.
84. Chen Z, Zhang YA. Cell therapy for macular degeneration–First phase I/II pluripotent stem cell-based clinical trial shows promise. Sci China Life Sci 2015;58:119–120.
85. Reardon S, Cyranoski D. Japan stem-cell trial stirs envy. Nature 2014;513:287–288.
86. Kanemura H, Go MJ, Shikamura M et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One 2014;9:e85336.
87. Cyranoski D. Japanese woman is first recipient of next-generation stem cells. Available at http://www.nature.com/news/japanese-woman-is-first-recipient-of-next-generation-stem-cells-1.15915. Accessed January 16, 2016.
88. Lee AS, Tang C, Rao MS et al. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med 2013;19:998–1004.
89. Huangfu D, Osafune K, Maehr R et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 2008;26:1269–1275.
90. Hirai H, Tani T, Katoku-Kikyo N et al. Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD. Stem Cells 2011;29:1349–1361.
91. Warren L, Ni Y, Wang J et al. Feeder-free derivation of human induced pluripotent stem cells with messenger RNA. Sci Rep 2012;2:657.
92. Liu X, Sun H, Qi J et al. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol 2013;15:829–838.
93. Sancho-Martinez I, Baek SH, Izpisua Belmonte JC. Lineage conversion methodologies meet the reprogramming toolbox. Nat Cell Biol 2012;14:892–899.
94. Muraoka N, Ieda M. Direct reprogramming of fibroblasts into myocytes to reverse fibrosis. Annu Rev Physiol 2014;76:21–37.
95. Qian L, Huang Y, Spencer CI et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012;485:593–598.
96. Szabo E, Rampalli S, Risueno RM et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 2010;468:521–526.
97. Zhou Q, Brown J, Kanarek A et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008;455:627–632.
98. Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 2011;475:390–393.
99. Simeonov KP, Uppal H. Direct reprogramming of human fibroblasts to hepatocyte-like cells by synthetic modified mRNAs. PLoS One 2014;9:e100134.
100. Vierbuchen T, Ostermeier A, Pang ZP et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463:1035–1041.
101. Kim H, Park Y, Lee JB. Self-assembled messenger RNA nanoparticles (mRNA-NPs) for efficient gene expression. Sci Rep 2015;5:12737.
102. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013;3:388–398.
103. Bringmann A, Held SA, Heine A et al. RNA vaccines in cancer treatment. J Biomed Biotechnol 2010;2010:623687.
104. Barrett DM, Zhao Y, Liu X et al. Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum Gene Ther 2011;22:1575–1586.
105. Beatty GL, Haas AR, Maus MV et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2014;2:112–120.
106. Kenderian SS, Ruella M, Shestova O et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 2015;29:1637–1647.
107. Michel T, Kankura A, Salinas Medina ML et al. In vitro evaluation of a novel mRNA-based therapeutic strategy for the treatment of patients suffering from alpha-1-antitrypsin deficiency. Nucleic Acid Ther 2015;25:235–244.
108. Schlake T, Thess A, Fotin-Mleczek M et al. Developing mRNA-vaccine technologies. RNA Biol 2012;9:1319–1330.
109. Rausch S, Schwentner C, Stenzl A et al. mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer. Hum Vaccin Immunother 2014;10:3146–3152.
110. Sebastian M, Papachristofilou A, Weiss C et al. Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(R)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer 2014;14:748.
111. Hellen CU, Sarnow P. Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev 2001;15:1593–1612.
112. Trichas G, Begbie J, Srinivas S. Use of the viral 2A peptide for bicistronic expression in transgenic mice. BMC Biol 2008;6:40–40.