Recent advances in the science of RNA production, purification, and intracellular delivery have enabled the development of RNA therapeutics. RNA therapies represent a rapidly expanding category of medicinal products that will change the standard treatment of many diseases, redefining the concept of personalized medicine. They may have great therapeutic potential in hereditary, oncological, and neurological diseases, metabolic diseases, etc. RNA therapies may provide better opportunities to target the underlying pathophysiological mechanisms of diseases, which in turn may lead to better therapeutic results. These medications are cost-effective to develop, relatively easy to manufacture, and hold potential for many presently incurable conditions. They are rapidly gaining traction in clinical practice.
In this comprehensive review, we discuss the general concepts of the different classes of RNA drugs and their pharmacological properties. Furthermore, we provide an overview of RNA drugs that have already received approval from regulatory bodies such as the FDA and EMA, shedding light on their pivotal role in modern medicine.
Dahm R. Friedrich Miescher and the discovery of DNA. Dev Biol. 2005;278(2):274-288. doi:10.1016/j.ydbio.2004.11.028
Cobb M. Who discovered messenger RNA? Curr Biol. 2015;25(13):R526-R532. doi:10.1016/j.cub.2015.05.032
Yu A-M, Choi YH, Tu M-J. RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. TOUYZ RM, ed. Pharmacol Rev. 2020;72(4):862-898. doi:10.1124/pr.120.019554
De Mey W, Esprit A, Thielemans K, Breckpot K, Franceschini L. RNA in Cancer Immunotherapy: Unlocking the Potential of the Immune System. Clin Cancer Res. 2022;28(18):3929-3939. doi:10.1158/1078-0432.CCR-21-3304
Damase TR, Sukhovershin R, Boada C, Taraballi F, Pettigrew RI, Cooke JP. The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol. 2021;9. doi:10.3389/fbioe.2021.628137
Dammes N, Peer D. Paving the Road for RNA Therapeutics. Tre1 Dammes N, Peer D Paving Road RNA Ther Trends Pharmacol Sci [Internet] 2020 Oct;41(10)755–75 Available from https//linkinghub.elsevier.com/retrieve/pii/S0165614720301851nds Pharmacol Sci. 2020;41(10):755-775. doi:10.1016/j.tips.2020.08.004
Kim Y-K. RNA therapy: rich history, various applications and unlimited future prospects. Exp Mol Med. 2022;54(4):455-465. doi:10.1038/s12276-022-00757-5
Shin H, Park S-J, Yim Y, et al. Recent Advances in RNA Therapeutics and RNA Delivery Systems Based on Nanoparticles. Adv Ther. 2018;1(7):1800065. doi:10.1002/adtp.201800065
Ghanbarian H, Aghamiri S, Eftekhary M, Wagner N, Wagner K-D. Small Activating RNAs: Towards the Development of New Therapeutic Agents and Clinical Treatments. Cells. 2021;10(3):591. doi:10.3390/cells10030591
Zogg H, Singh R, Ro S. Current Advances in RNA Therapeutics for Human Diseases. Int J Mol Sci. 2022;23(5):2736. doi:10.3390/ijms23052736
Youn H, Chung J-K. Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. Expert Opin Biol Ther. 2015;15(9):1337-1348. doi:10.1517/14712598.2015.1057563
Magadum A, Kaur K, Zangi L. mRNA-Based Protein Replacement Therapy for the Heart. Mol Ther. 2019;27(4):785-793. doi:10.1016/j.ymthe.2018.11.018
Versteeg L, Almutairi MM, Hotez PJ, Pollet J. Enlisting the mRNA Vaccine Platform to Combat Parasitic Infections. Vaccines. 2019;7(4):122. doi:10.3390/vaccines7040122
Qin S, Tang X, Chen Y, et al. mRNA-based therapeutics: powerful and versatile tools to combat diseases. Signal Transduct Target Ther. 2022;7(1):166. doi:10.1038/s41392-022-01007-w
Sahin U, Oehm P, Derhovanessian E, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature. 2020;585(7823):107-112. doi:10.1038/s41586-020-2537-9
Van Hoecke L, Roose K. How mRNA therapeutics are entering the monoclonal antibody field. J Transl Med. 2019;17(1):54. doi:10.1186/s12967-019-1804-8
Dammes N, Peer D. Paving the Road for RNA Therapeutics. Trends Pharmacol Sci. 2020;41(10):755-775. doi:10.1016/j.tips.2020.08.004
Liang X, Li D, Leng S, Zhu X. RNA-based pharmacotherapy for tumors: From bench to clinic and back. Biomed Pharmacother. 2020;125:109997. doi:10.1016/j.biopha.2020.109997
Dhuri K, Bechtold C, Quijano E, et al. Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J Clin Med. 2020;9(6):2004. doi:10.3390/jcm9062004
Crooke ST. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic Acid Ther. 2017;27(2):70-77. doi:10.1089/nat.2016.0656
Dana H, Chalbatani GM, Mahmoodzadeh H, et al. Molecular Mechanisms and Biological Functions of siRNA. Int J Biomed Sci. 2017;13(2):48-57. http://www.ncbi.nlm.nih.gov/pubmed/28824341
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610. doi:10.1038/nrg2843
Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr Opin Cell Biol. 2009;21(3):452-460. doi:10.1016/j.ceb.2009.04.009
Cammaerts S, Strazisar M, De Rijk P, Del Favero J. Genetic variants in microRNA genes: impact on microRNA expression, function, and disease. Front Genet. 2015;6. doi:10.3389/fgene.2015.00186
Palmero EI, Campos SGP de, Campos M, et al. Mechanisms and role of microRNA deregulation in cancer onset and progression. Genet Mol Biol. 2011;34(3):363-370. doi:10.1590/S1415-47572011000300001
MacLeod AR, Crooke ST. RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions. J Clin Pharmacol. 2017;57:S43-S59. doi:10.1002/jcph.957
Si W, Shen J, Zheng H, Fan W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics. 2019;11(1):25. doi:10.1186/s13148-018-0587-8
Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y. Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy. Mol Ther - Nucleic Acids. 2014;3:e182. doi:10.1038/mtna.2014.32
Germer K, Leonard M, Zhang X. RNA aptamers and their therapeutic and diagnostic applications. Int J Biochem Mol Biol. 2013;4(1):27-40. http://www.ncbi.nlm.nih.gov/pubmed/23638319
Sheng L, Rigo F, Bennett CF, Krainer AR, Hua Y. Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model. Nucleic Acids Res. 2020;48(6):2853-2865. doi:10.1093/nar/gkaa126
Pastor F. Aptamers: A New Technological Platform in Cancer Immunotherapy. Pharmaceuticals. 2016;9(4):64. doi:10.3390/ph9040064
Han J, Gao L, Wang J, Wang J. Application and development of aptamer in cancer: from clinical diagnosis to cancer therapy. J Cancer. 2020;11(23):6902-6915. doi:10.7150/jca.49532
Ni S, Yao H, Wang L, et al. Chemical Modifications of Nucleic Acid Aptamers for Therapeutic Purposes. Int J Mol Sci. 2017;18(8):1683. doi:10.3390/ijms18081683
Kumar Kulabhusan P, Hussain B, Yüce M. Current Perspectives on Aptamers as Diagnostic Tools and Therapeutic Agents. Pharmaceutics. 2020;12(7):646. doi:10.3390/pharmaceutics12070646
Dowdy SF. Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol. 2017;35(3):222-229. doi:10.1038/nbt.3802
Titze-de-Almeida R, David C, Titze-de-Almeida SS. The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Pharm Res. 2017;34(7):1339-1363. doi:10.1007/s11095-017-2134-2
Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int. 2020;20(1):16. doi:10.1186/s12935-019-1091-8
Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004;432(7014):173-178. doi:10.1038/nature03121
Paunovska K, Loughrey D, Dahlman JE. Drug delivery systems for RNA therapeutics. Nat Rev Genet. 2022;23(5):265-280. doi:10.1038/s41576-021-00439-4
Ickenstein LM, Garidel P. Lipid-based nanoparticle formulations for small molecules and RNA drugs. Expert Opin Drug Deliv. 2019;16(11):1205-1226. doi:10.1080/17425247.2019.1669558
Dowdy SF. Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem? RNA. 2023;29(4):396-401. doi:10.1261/rna.079507.122
Matsuda S, Keiser K, Nair JK, et al. siRNA Conjugates Carrying Sequentially Assembled Trivalent N- Acetylgalactosamine Linked Through Nucleosides Elicit Robust Gene Silencing In Vivo in Hepatocytes. ACS Chem Biol. 2015;10(5):1181-1187. doi:10.1021/cb501028c
Rajeev KG, Nair JK, Jayaraman M, et al. Hepatocyte-Specific Delivery of siRNAs Conjugated to Novel Non-nucleosidic Trivalent N -Acetylgalactosamine Elicits Robust Gene Silencing in Vivo. ChemBioChem. 2015;16(6):903-908. doi:10.1002/cbic.201500023
Lapinaite A, Doudna JA, Cate JHD. Programmable RNA recognition using a CRISPR-associated Argonaute. Proc Natl Acad Sci. 2018;115(13):3368-3373. doi:10.1073/pnas.1717725115
Zlatev I, Castoreno A, Brown CR, et al. Reversal of siRNA-mediated gene silencing in vivo. Nat Biotechnol. 2018;36(6):509-511. doi:10.1038/nbt.4136
Rohner E, Yang R, Foo KS, Goedel A, Chien KR. Unlocking the promise of mRNA therapeutics. Nat Biotechnol. 2022;40(11):1586-1600. doi:10.1038/s41587-022-01491-z
Perry CM, Barman Balfour JA. Fomivirsen. Drugs. 1999;57(3):375-380. doi:10.2165/00003495-199957030-00010
Vitravene. https://www.ema.europa.eu/en/medicines/human/EPAR/vitravene
Kynamro_Prescribing_information.pdf. Published 2013. https://www.kynamro.com/media/pdfs/Kynamro_Prescribing_information.pdf
Refusal of the marketing authorisation for Kynamro (mipomersen). Published 2013. https://wwhttps//www.ema.europa.eu/en/documents/smop-initial/questions-answers-refusal-marketing-authorisation-kynamro-outcome-re-examination_en.pdfw.ema.europa.eu/en/medicines/human/EPAR/kynamro
Spinraza nusinersen Резюме на EPAR за обществено ползване. Published 2017. https://www.ema.europa.eu/en/documents/overview/spinraza-epar-summary-public_bg.pdf
Spinraza КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. https://www.ema.europa.eu/en/documents/product-information/spinraza-epar-product-information_bg.pdf
EXONDYS 51 (eteplirsen) Prescribing information. Published 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206488s019lbl.pdf
Anthony K, Feng L, Arechavala-Gomeza V, et al. Exon Skipping Quantification by Quantitative Reverse-Transcription Polymerase Chain Reaction in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen. Hum Gene Ther Methods. 2012;23(5):336-345. doi:10.1089/hgtb.2012.117
Tegsedi Кратка характеристика. https://www.ema.europa.eu/en/documents/product-information/tegsedi-epar-product-information_bg.pdf
VYONDYS 53 (golodirsen) prescribing information. Published 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211970s002lbl.pdf
Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019;381(17):1644-1652. doi:10.1056/NEJMoa1813279
AMONDYS 45 (casimersen) prescribing information. Published 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213026lbl.pdf
Onpattro КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2018. https://www.ema.europa.eu/en/documents/product-information/onpattro-epar-product-information_bg.pdf
Givlaari КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2020. https://www.ema.europa.eu/en/documents/product-information/givlaari-epar-product-information_bg.pdf
Oxlumo КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2020. https://www.ema.europa.eu/en/documents/product-information/oxlumo-epar-product-information_bg.pdf
Leqvio КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2020. https://www.ema.europa.eu/en/documents/product-information/leqvio-epar-product-information_bg.pdf
Amvuttra КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2022. https://www.ema.europa.eu/en/documents/product-information/amvuttra-epar-product-information_bg.pdf
Macugen КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2015. https://www.ema.europa.eu/en/documents/product-information/macugen-epar-product-information_bg.pdf
Comirnaty КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2022. https://www.ema.europa.eu/en/documents/product-information/comirnaty-epar-product-information_bg.pdf
Spikevax КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА. Published 2022. https://www.ema.europa.eu/en/documents/product-information/spikevax-previously-covid-19-vaccine-moderna-epar-product-information_bg.pdf
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