RNA-Based Therapeutic Approaches

Abstract

RNA-based therapeutics constitute therapeutic strategies with very high potential, thanks to the elucidation of the mechanisms of action of RNA molecules in cellular processes and developing technology. These strategies offer new alternatives regarding the mechanisms, pathophysiological processes, diagnosis, treatment and prevention of many diseases. It also opens new doors to many pathophysiological pathways previously known as "untargetable". Thanks to the various molecular-based agents provided by RNA-based therapeutics, promising new treatment methods can be developed for diseases for which treatment is inadequate. Today, 16 known FDA-approved RNA therapeutic drugs are used in clinics. In addition, many RNA therapeutics are under development, which will open the door to new treatment methods for many diseases in the near future. In this review article, topics such as the mechanism, synthesis, packaging, and target delivery of currently used RNA therapeutic strategies are investigated, and candidate therapeutic strategies are also mentioned.

Keywords

• ASO
• Oligonucleotide
• RNA
• siRNA
• Therapeutic

RNA Temelli Terapötik Yaklaşımlar

Abstract

RNA temelli terapötikler, RNA moleküllerinin hücresel süreçlerdeki etki mekanizmalarının aydınlatılması ve gelişen teknoloji ile oldukça yüksek potansiyele sahip terapötik stratejileri oluşturmaktadır. Bu stratejiler, birçok hastalığın mekanizması, patofizyolojik süreçleri, teşhisi, tedavisi ve hastalığın önlenmesi konusunda yeni alternatifler sunmaktadır. Ayrıca daha önce ‘‘hedeflenemez’’ olarak bilinen birçok patofizyolojik yollara yeni kapılar açmaktadır. RNA bazlı terapötiklerin sağladığı çeşitli moleküler bazlı ajanlar sayesinde tedavisi yeterli düzeyde olmayan hastalıklara umut verici yeni tedavi yöntemleri geliştirlebilecektir. Günümüzde bilinen 16 adet FDA onaylı RNA terapötik ilaç klinikte kullanılmaktadır. Bunun yanında çok sayıda RNA terapötiği geliştirilme aşamasındadır ve bu durum yakın gelecekte birçok hastalık için yeni tedavi yöntemlerine kapı açacaktır. Bu derleme makalesinde halihazırda kullanılan RNA terapötik stratejilerinin mekanizması, sentezlenmesi, paketlenmesi, hedefe iletimi gibi konular araştırılmıştır ve bunun yanında aday terapötik stratejilere de değinilmiştir.

Keywords

• ASO
• Oligonükleotid
• RNA
• siRNA
• Terapötik

References

1. 1. Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nat. 2012; 489(7414): 101-108.
2. 2. Pamudurti NR, Bartok O, Jens M, et al. Translation of circRNAs. Mol Cell. 2017; 66(1): 9-21.
3. 3. Dai X, Zhang S, Zaleta-Rivera K. RNA: interactions drive functionalities. Mol Biol Rep. 2020; 47(2): 1413-1434.
4. 4. Brenner S, Jacob F, Meselson M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nat. 1961; 190(4776): 576-581.
5. 5. Gros F, Hiatt H, Gilbert W, Kurland CG, Risebrough RW, Watson JD. Unstable ribonucleic acid revealed by pulse labelling of Escherichia coli. Nat. 1961; 190(4776): 581-585.
6. 6. Chow LT, Gelinas RE, Broker TR, Roberts RJ. An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell. 1977; 12(1): 1-8.
7. 7. Kruger K, Grabowski PJ, Zaug AJ, Sands J, Gottschling DE, Cech TR. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell. 1982; 31(1): 147-157.
8. 8. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75(5): 843-854.

9. 9. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nat. 1998; 391(6669): 806-811.
10. 10. Ban N, Nissen P, Hansen J, Moore PB, Steitz TA. The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution. Science. 2000; 289(5481): 905-920.
11. 11. Schluenzen F, Tocilj A, Zarivach R, et al. Structure of functionally activated small ribosomal subunit at 3.3 Å resolution. Cell. 2000; 102(5): 615-623.
12. 12. Wimberly BT, Brodersen DE, Clemons WM, et al. Structure of the 30S ribosomal subunit. Nat. 2000; 407(6802): 327-339.
13. 13. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337(6096): 816-821.
14. 14. Zhang C, Zhang B. RNA therapeutics: updates and future potential. Sci China Life Sci. 2023. 66(1): 12-30.
15. 15. Lieberman J. Tapping the RNA world for therapeutics. Nat Struct Mol Biol. 2018; 25(5): 357-364.
16. 16. Qadir MI, Bukhat S, Rasul S, Manzoor H, Manzoor M. RNA therapeutics: Identification of novel targets leading to drug discovery. J Cell Biochem. 2020; 121(2): 898-929.
17. 17. Bejar N, Tat TT, Kiss DL. RNA Therapeutics: the Next Generation of Drugs for Cardiovascular Diseases. Curr Atheroscler Rep. 2022; 24(5): 1-15.
18. 18. Robinson EL, Port JD. Utilization and Potential of RNA-Based Therapies in Cardiovascular Disease. JACC Basic Transl Sci. 2022; 7(9): 956-969.
19. 19. Shin H, Park SJ, Yim Y, et al. Recent advances in RNA therapeutics and RNA delivery systems based on nanoparticles. Adv Ther. 2018; 1(7): 1800065.
20. 20. Agrawal S. RNA therapeutics are stepping out of the maze. Trends Mol Med. 2020; 26(12): 1061-1064.
21. 21. Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. Genome Biol. 2002; 3(3): 1-10.
22. 22. Zogg H, Singh R, Ro S. Current Advances in RNA Therapeutics for Human Diseases. Int J Mol Sci. 2022; 23(5): 2736.
23. 23. Gao M, Zhang Q, Feng XH, Liu J. Synthetic modified messenger RNA for therapeutic applications. Acta Biomater. 2021; 131: 1-15.
24. 24. Leppek K, Das R, Barna M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol. 2018; 19(3): 158-174.
25. 25. Da Silva Sanchez A, Paunovska K, Cristian A, Dahlman JE. Treating cystic fibrosis with mRNA and CRISPR. Hum Gene Ther. 2020; 31(17-18): 940-955.
26. 26. Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990; 247(4949): 1465-1468.
27. 27. Weng Y, Li C, Yang T, et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol Adv. 2020; 40: 107534.
28. 28. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. Three decades of messenger RNA vaccine development. Nano Today. 2019; 28: 100766.
29. 29. Warren L, Lin C. mRNA-based genetic reprogramming. Mol Ther. 2019; 27(4): 729-734.
30. 30. Maruggi G, Zhang C, Li J, Ulmer JB, Yu D. mRNA as a transformative technology for vaccine development to control infectious diseases. Mol Ther. 2019; 27(4): 757-772.
31. 31. Kwon H, Kim M, Seo Y, et al. Emergence of synthetic mRNA: In vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials. 2018; 156: 172-193.
32. 32. Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat Rev Mater. 2017; 2(10): 1-17.
33. 33. Sergeeva OV, Koteliansky VE, Zatsepin TS. mRNA-based therapeutics–Advances and perspectives. Biochemistry (Mosc). 2016; 81(7): 709-722.
34. 34. Vallazza B, Petri S, Poleganov MA, Eberle F, Kuhn AN, Sahin U. Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond. Wiley Interdiscip Rev RNA. 2015; 6(5): 471-499.
35. 35. Chaudhary N, Weissman D, Whitehead KA. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat Rev Drug Discov. 2021; 20(11): 817-838.
36. 36. Zhu Y, Zhu L, Wang X, Jin H. RNA-based therapeutics: An overview and prospectus. Cell Death Dis. 2022; 13(7): 1-15.
37. 37. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class of drugs. Nat Rev Drug Discov. 2014; 13(10): 759-780.
38. 38. Nelson J, Sorensen EW, Mintri S, et al. Impact of mRNA chemistry and manufacturing process on innate immune activation. Sci Adv. 2020; 6: 26.
39. 39. Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proceedings of the National Academy of Sciences. 1978; 75(1): 280-284.
40. 40. Rinaldi C, Wood MJ. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018; 14(1): 9-21.
41. 41. Glazier DA, Liao J, Roberts BL, et al. Chemical synthesis and biological application of modified oligonucleotides. Bioconjug Chem. 2020; 31(5): 1213-1233.
42. 42. Misra A. Challenges in delivery of therapeutic genomics and proteomics. Elsevier London United Kingdom. 2010; pp: 671.
43. 43. Kim YK. RNA therapy: current status and future potential. Chonnam Med J. 2020; 56(2): 87.
44. 44. Zhou J, Bobbin ML, Burnett JC, Rossi JJ. Current progress of RNA aptamer-based therapeutics. Front Genet. 2012; 3: 234.
45. 45. Dammes N, Peer D. Paving the road for RNA therapeutics. Trends Pharmacol Sci. 2020; 41(10): 755-775.
46. 46. Mollocana-Lara EC, Ni M, Agathos SN, Gonzales-Zubiate FA. The infinite possibilities of RNA therapeutics. J Ind Microbiol Biotechnol. 2021; 48: 9-10.
47. 47. Quemener AM. Bachelot L, Forestier A, Donnou‐Fournet E, Gilot D, Galibert MD. The powerful world of antisense oligonucleotides: From bench to bedside. Wiley Interdiscip Rev RNA. 2020; 11(5): e1594.
48. 48. Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016; 44(14): 6549-6563.
49. 49. Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019; 42: 385.
50. 50. Hirunagi T, Sahashi K, Tachikawa K, et al. Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS. Mol Ther Nucleic Acids. 2021; 24: 1-10.
51. 51. Brown KM, Nair JK, Janas MM, et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol. 2022; 40(10): 1500-1508
52. 52. Germain ND, Chung WK, Sarmiere PD. RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases. Mol Aspects Med. 2022; 91: 101148.
53. 53. Schwarz DS, Ding H, Kennington L, et al. Designing siRNA that distinguish between genes that differ by a single nucleotide. PLoS Genet. 2006; 2(9): e140.
54. 54. McCullough SD, Dolinoy D. Toxicoepigenetics: Core principles and applications. Academic Press London United Kingdom. 2018; pp: 326.
55. 55. Xu JZ, Zhang JL, Zhang WG. Antisense RNA: the new favorite in genetic research. J Zhejiang Univ Sci B. 2018; 19(10): 739-749.
56. 56. Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov. 2010; 9(1): 57-67.
57. 57. Grimm D. The dose can make the poison: lessons learned from adverse in vivotoxicities caused by RNAi overexpression. Silence. 2011; 2(1): 1-6.
58. 58. Chakraborty C, Sharma AR, Sharma G, Doss CGP, Lee SS. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids. 2017; 8: 132-143.
59. 59. Bajan S, Hutvagner G. RNA-based therapeutics: from antisense oligonucleotides to miRNAs. Cells. 2020; 9(1): 137.
60. 60. Grimm D, Streetz KL, Jopling CL, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nat. 2006; 441(7092): 537-541.
61. 61. Powell SK, Rivera-Soto R, Gray SJ. Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy. Discov Med. 2015; 19(102): 49.
62. 62. Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics—Challenges and potential solutions. Nat Rev Drug Discov. 2021; 20(8): 629-651.
63. 63. Yekta S, Shih IH, Bartel DP. MicroRNA-directed cleavage of HOXB8 mRNA. Science. 2004; 304(5670): 594-596.
64. 64. Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet. 2015; 16(7): 421-433.
65. 65. Shigdar S, Ward AC, De A, Yang CJ, Wei M, Duan W. Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies. Br J Haematol. 2011; 155(1): 3-13.
66. 66. Zhu Q, Liu G, Kai M. DNA aptamers in the diagnosis and treatment of human diseases. Molecules. 2015; 20(12): 20979-20997.
67. 67. Missailidis S, Hardy A. Aptamers as inhibitors of target proteins. Expert Opin Ther Pat. 2009; 19(8): 1073-1082.
68. 68. Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov. 2010; 9(7): 537-550.
69. 69. Leirdal M, Sioud M. Gene silencing in mammalian cells by preformed small RNA duplexes. Biochem Biophys Res Commun. 2002; 295(3): 744-748.
70. 70. Sioud M. Ribozymes and siRNA protocols. Springer, Vol. 252. Methods Mol Biol, Humana Press, Totowa NJ, 2004; pp: 277.
71. 71. Haussecker D. Current issues of RNAi therapeutics delivery and development. J Control Release. 2014; 195: 49-54.
72. 72. Shukla S, Sumaria CS, Pradeepkumar PI. Exploring chemical modifications for siRNA therapeutics: a structural and functional outlook. Chem Med Chem. 2010; 5(3): 328-349.
73. 73. Egli M, Manoharan M. Re-engineering RNA molecules into therapeutic agents. Acc Chem Res. 2019; 52(4): 1036-1047.
74. 74. Judge AD, Bola G, Lee AC, MacLachlan I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther. 2006; 13(3): 494-505.
75. 75. Jackson AL, Burchard J, Schelter J, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. Rna, 2006; 12(7): 1179-1187.
76. 76. Davis S, Lollo B, Freier S, Esau C. Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res. 2006; 34(8): 2294-2304.
77. 77. Esau C, Davis S, Murray SF, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006; 3(2): 87-98.
78. 78. Ørom UA, Kauppinen S, Lund AH. LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene. 2006; 372: 137-141.
79. 79. Lennox KA, Behlke MA. A direct comparison of anti-microRNA oligonucleotide potency. Pharm Res. 2010; 27(9): 1788-1799.
80. 80. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab. 2018; 27(4): 714-739.
81. 81. Dowdy SF. Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol. 2017; 35(3): 222-229.
82. 82. Roberts TC, Langer R, Wood MJ. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020; 19(10): 673-694.
83. 83. Shi Y, Jia X, Xu J. The new function of circRNA: translation. Clin Transl Oncol. 2020; 22(12): 2162-2169.
84. 84. Zganiacz D, Milanowski R. Characteristics of circular ribonucleic acid molecules (circRNA). Postepy Biochem. 2017; 63(3): 221-232.
85. 85. Liu CX, Chen LL. Circular RNAs: Characterization, cellular roles, and applications. Cell. 2022; 185(12): 2016–2034
86. 86. Zhang Y, Xue W, Li X, et al. The biogenesis of nascent circular RNAs. Cell Rep. 2016; 15(3): 611-624.
87. 87. Litke JL, Jaffrey SR. Highly efficient expression of circular RNA aptamers in cells using autocatalytic transcripts. Nat Biotechnol. 2019; 37(6): 667-675.
88. 88. Lavenniah A, Luu TDA, Li YP, et al. Engineered circular RNA sponges act as miRNA inhibitors to attenuate pressure overload-induced cardiac hypertrophy. Mole Ther. 2020; 28(6): 1506-1517.
89. 89. Espinoza S, Bon C, Valentini P, et al. SINEUPs: a novel toolbox for RNA therapeutics. Essays Biochem. 2021; 65(4): 775-789.
90. 90. Uszczynska-Ratajczak B, Lagarde J, Frankish A, Guigó R, Johnson R. Towards a complete map of the human long non-coding RNA transcriptome. Nat Rev Genet. 2018; 19(9): 535-548.
91. 91.Battistelli C, Cicchini C, Santangelo L, et al. The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene. 2017; 36(7): 942-955.
92. 92.Fazi B, Garbo S, Toschi N, et al. The lncRNA H19 positivelyaffects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter. Oncotarget. 2018; 9(21): 15512.
93. 93.Battistelli C, Sabarese G, Santangelo L, et al. The lncRNA HOTAIR transcription is controlled by HNF4α-induced chromatin topology modulation. Cell Death Differ. 2019; 26(5): 890-901.
94. 94.Andresini O, Rossi MN, Matteini F, Petrai S, Santini T, Maione R.The long non-coding RNA Kcnq1ot1 controls maternal p57 expression in muscle cells by promoting H3K27me3accumulation to an intragenic MyoD-binding region. Epigenetics Chromatin. 2019; 12(1): 1-16.
95. 95.Tay Y, Rinn J, Pandolfi PP. The multilayered complexity ofceRNA crosstalk and competition. Nat. 2014; 505(7483): 344-352.
96. 96.Garbo S, Maione R, Tripodi M, Battistelli C. Next RNAtherapeutics: the mine of non-coding. Int J Mol Sci. 2022; 23(13): 7471.
97. 97.Amodio N, Stamato MA, Juli G, et al. Drugging the lncRNAMALAT1 via LNA gapmeR ASO inhibits gene expression ofproteasome subunits and triggers anti-multiple myeloma activity. Leukemia. 2018; 32(9): 1948-1957.
98. 98.Zucchelli S, Cotella D, Takahashi H, et al. SINEUPs: A new class of natural and synthetic antisense long non-coding RNAsthat activate translation. RNA Biol. 2015; 12(8): 771-779.
99. 99.Liu X, Zhang Y, Zhou S, Dain L, Mei L, Zhu G. Circular RNA:An emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines. J Control Release. 2022; 348: 84-94.
100. 100. Dzierlega K, Yokota T. Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy. Gene Ther. 2020; 27(9): 407-416.
101. 101. Senti ME, Del Valle LG, Schiffelers RM. mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond. Advanced Drug Delivery Reviews, 2024; 115190.