myrwdРеальная клиническая практика: данные и доказательстваReal-World Data & Evidence2782-3784Publishing House OKI10.37489/2782-3784-myrwd-46XVNITYmyrwd-60Research ArticleАКТУАЛЬНЫЕ ОБЗОРЫACTUAL REVIEWМалая интерферирующая РНК: потенциал использования в условиях реальной клинической практикиSmall interfering RNA: potential in real-world clinical practicehttps://orcid.org/0000-0003-2863-792XМотринчукА. Ш.MotrinchukA. S.

Мотринчук Айтэн Шерифовна — ординатор кафедры клинической фармакологии и доказательной медицины

Санкт-Петербург

Aiten S. Motrinchuk — Resident of the department of Clinical Pharmacology and Evidence-Based Medicine

St. Petersburg

aitesha555@yandex.ruhttps://orcid.org/0000-0001-6284-7133КасимоваА. Р.KasimovaA. R.

Касимова Алина Рашидовна — к. м. н., доцент кафедры клинической фармакологии и доказательной медицины, врач — клинический фармаколог отделения клинической фармакологии

Санкт-Петербург

Alina R. Kasimova — PhD, associate professor of the department of Clinical Pharmacology and Evidence-Based Medicine, Clinical pharmacologist of the Department of Clinical Pharmacology

St. Petersburg

kasi-alina@yandex.ruФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова» Министерства здравоохранения Российской ФедерацииРоссияFirst St. Petersburg State Medical University named after Academician I.P. PavlovRussian FederationФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова» Министерства здравоохранения Российской Федерации; ФГБУ «Национальный медицинский исследовательский центр травматологии и ортопедии имени Р. Р. Вредена» Министерства здравоохранения Российской ФедерацииРоссияFirst St. Petersburg State Medical University named after Academician I.P. Pavlov; National Medical Research Center for Traumatology and Orthopedics named after R.R. VredenRussian Federation20243003202441313Copyright © Мотринчук А.Ш., Касимова А.Р., 20242024Мотринчук А.Ш., Касимова А.Р.Motrinchuk A.S., Kasimova A.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.myrwd.ru/jour/article/view/60

В данном обзоре описываются основы биосинтеза белка и процессы РНК-интерференции, рассматриваются полезные и уникальные свойства миРНК-терапии, её преимущества и недостатки в сравнении с другими методами сайленсинга генов, даётся краткий обзор техническим достижениям и модификациям миРНК-терапии, а также характеристика миРНК-зарегистрированных лекарственных средств и средств, находящихся на разных этапах клинических исследований.

This review describes the basics of protein biosynthesis and RNA interference processes, discusses the useful and unique properties of siRNA therapy, its advantages and disadvantages in comparison with other gene silencing methods, provides a brief overview of technical advances and modifications of siRNA therapy, and characterizes siRNA-registered drugs and agents at different stages of clinical trials.

миРНКРНК-интерференцияsiRNARNA interferenceReferencesDahm R. Friedrich Miescher and the discovery of DNA. Dev Biol. 2005 Feb 15;278(2):274-88. doi: 10.1016/j.ydbio.2004.11.028.Dahm R. Friedrich Miescher and the discovery of DNA. Dev Biol. 2005 Feb 15;278(2):274-88. doi: 10.1016/j.ydbio.2004.11.028.Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953 Apr 25;171(4356):737-8. doi: 10.1038/171737a0.Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953 Apr 25;171(4356):737-8. doi: 10.1038/171737a0.Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998 Feb 19;391(6669): 806-11. doi: 10.1038/35888.Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998 Feb 19;391(6669): 806-11. doi: 10.1038/35888.Liu Y, Liu J, Quimbo A, Xia F, Yao J, Clamme JP, Zabludoff S, Zhang J, Ying W. Anti-HSP47 siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis in preclinical rat models. ERJ Open Res. 2021 Jun 7;7(2):00733-2020. doi: 10.1183/23120541.00733-2020.Liu Y, Liu J, Quimbo A, Xia F, Yao J, Clamme JP, Zabludoff S, Zhang J, Ying W. Anti-HSP47 siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis in preclinical rat models. ERJ Open Res. 2021 Jun 7;7(2):00733-2020. doi: 10.1183/23120541.00733-2020.Sheu-Gruttadauria J, MacRae IJ. Structural Foundations of RNA Silencing by Argonaute. J Mol Biol. 2017 Aug 18;429(17):2619-2639. doi: 10.1016/j.jmb.2017.07.018.Sheu-Gruttadauria J, MacRae IJ. Structural Foundations of RNA Silencing by Argonaute. J Mol Biol. 2017 Aug 18;429(17):2619-2639. doi: 10.1016/j.jmb.2017.07.018.Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, Wijngaard P, Horton JD, Taubel J, Brooks A, Fernando C, Kauffman RS, Kallend D, Vaishnaw A, Simon A. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017 Jan 5;376(1):41-51. doi: 10.1056/NEJMoa1609243.Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, Wijngaard P, Horton JD, Taubel J, Brooks A, Fernando C, Kauffman RS, Kallend D, Vaishnaw A, Simon A. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017 Jan 5;376(1):41-51. doi: 10.1056/NEJMoa1609243.Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147.Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147.Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520-1530. doi: 10.1056/NEJMoa1913805.Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520-1530. doi: 10.1056/NEJMoa1913805.Leng Q, Woodle MC, Mixson AJ. Targeted Delivery of siRNA Therapeutics to Malignant Tumors. J Drug Deliv. 2017;2017:6971297. doi: 10.1155/2017/6971297.Leng Q, Woodle MC, Mixson AJ. Targeted Delivery of siRNA Therapeutics to Malignant Tumors. J Drug Deliv. 2017;2017:6971297. doi: 10.1155/2017/6971297.Huang Y, Hong J, Zheng S, Ding Y, Guo S, Zhang H, Zhang X, Du Q, Liang Z. Elimination pathways of systemically delivered siRNA. Mol Ther. 2011 Feb;19(2):381-5. doi: 10.1038/mt.2010.266.Huang Y, Hong J, Zheng S, Ding Y, Guo S, Zhang H, Zhang X, Du Q, Liang Z. Elimination pathways of systemically delivered siRNA. Mol Ther. 2011 Feb;19(2):381-5. doi: 10.1038/mt.2010.266.Lau S, Graham B, Cao N, Boyd BJ, Pouton CW, White PJ. Enhanced extravasation, stability and in vivo cardiac gene silencing via in situ siRNA-albumin conjugation. Molecular Pharmaceutics. 2012;9(1):71-80. doi: 10.1021/mp2002522.Lau S, Graham B, Cao N, Boyd BJ, Pouton CW, White PJ. Enhanced extravasation, stability and in vivo cardiac gene silencing via in situ siRNA-albumin conjugation. Molecular Pharmaceutics. 2012;9(1):71-80. doi: 10.1021/mp2002522.Sun Y, Zhao Y, Zhao X, Lee RJ, Teng L, Zhou C. Enhancing the Therapeutic Delivery of Oligonucleotides by Chemical Modification and Nanoparticle Encapsulation. Molecules. 2017; 22(10):1724. https://doi.org/10.3390/molecules22101724.Sun Y, Zhao Y, Zhao X, Lee RJ, Teng L, Zhou C. Enhancing the Therapeutic Delivery of Oligonucleotides by Chemical Modification and Nanoparticle Encapsulation. Molecules. 2017; 22(10):1724. https://doi.org/10.3390/molecules22101724.Cedillo I, Chreng D, Engle E, Chen L, McPherson AK, Rodriguez AA. Synthesis of 5'-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies. Molecules. 2017 Aug 15;22(8):1356. doi: 10.3390/molecules22081356.Cedillo I, Chreng D, Engle E, Chen L, McPherson AK, Rodriguez AA. Synthesis of 5'-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies. Molecules. 2017 Aug 15;22(8):1356. doi: 10.3390/molecules22081356.Selvam C, Mutisya D, Prakash S, Ranganna K, Thilagavathi R. Therapeutic potential of chemically modified siRNA: Recent trends. Chem Biol Drug Des. 2017 Nov;90(5):665-678. doi: 10.1111/cbdd.12993.Selvam C, Mutisya D, Prakash S, Ranganna K, Thilagavathi R. Therapeutic potential of chemically modified siRNA: Recent trends. Chem Biol Drug Des. 2017 Nov;90(5):665-678. doi: 10.1111/cbdd.12993.Amarzguioui M, Holen T, Babaie E, Prydz H. Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res. 2003 Jan 15;31(2):589-95. doi: 10.1093/nar/gkg147.Amarzguioui M, Holen T, Babaie E, Prydz H. Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res. 2003 Jan 15;31(2):589-95. doi: 10.1093/nar/gkg147.Wu J, Yang J, Cho WC, Zheng Y. Argonaute proteins: Structural features, functions and emerging roles. J Adv Res. 2020 Apr 29;24:317-324. doi: 10.1016/j.jare.2020.04.017.Wu J, Yang J, Cho WC, Zheng Y. Argonaute proteins: Structural features, functions and emerging roles. J Adv Res. 2020 Apr 29;24:317-324. doi: 10.1016/j.jare.2020.04.017.Anderson BR, Muramatsu H, Nallagatla SR, Bevilacqua PC, Sansing LH, Weissman D, Karikó K. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. 2010 Sep;38(17):5884-92. doi: 10.1093/nar/gkq347.Anderson BR, Muramatsu H, Nallagatla SR, Bevilacqua PC, Sansing LH, Weissman D, Karikó K. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. 2010 Sep;38(17):5884-92. doi: 10.1093/nar/gkq347.Selvam C, Mutisya D, Prakash S, Ranganna K, Thilagavathi R. Therapeutic potential of chemically modified siRNA: Recent trends. Chem Biol Drug Des. 2017 Nov;90(5):665-678. doi: 10.1111/cbdd.12993.Selvam C, Mutisya D, Prakash S, Ranganna K, Thilagavathi R. Therapeutic potential of chemically modified siRNA: Recent trends. Chem Biol Drug Des. 2017 Nov;90(5):665-678. doi: 10.1111/cbdd.12993.Bramsen JB, Laursen MB, Damgaard CK, Lena SW, Babu BR, Wengel J et al. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Research. 2007;35(17):5886-5897. doi: 10.1093/nar/gkm548.Bramsen JB, Laursen MB, Damgaard CK, Lena SW, Babu BR, Wengel J et al. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Research. 2007;35(17):5886-5897. doi: 10.1093/nar/gkm548.Cheng CJ, Tietjen GT, Saucier-Sawyer JK, Saltzman WM. A holistic approach to targeting disease with polymeric nanoparticles. Nat Rev Drug Discov. 2015 Apr;14(4):239-47. doi: 10.1038/nrd4503.Cheng CJ, Tietjen GT, Saucier-Sawyer JK, Saltzman WM. A holistic approach to targeting disease with polymeric nanoparticles. Nat Rev Drug Discov. 2015 Apr;14(4):239-47. doi: 10.1038/nrd4503.Tatiparti K, Sau S, Kashaw SK, Iyer AK. siRNA Delivery Strategies: A Comprehensive Review of Recent Developments. Nanomaterials (Basel). 2017 Apr 5;7(4):77. doi: 10.3390/nano7040077.Tatiparti K, Sau S, Kashaw SK, Iyer AK. siRNA Delivery Strategies: A Comprehensive Review of Recent Developments. Nanomaterials (Basel). 2017 Apr 5;7(4):77. doi: 10.3390/nano7040077.Bryson TE, Anglin CM, Bridges PH, Cottle RN. Nuclease-Mediated Gene Therapies for Inherited Metabolic Diseases of the Liver. Yale J Biol Med. 2017 Dec 19;90(4):553-566.Bryson TE, Anglin CM, Bridges PH, Cottle RN. Nuclease-Mediated Gene Therapies for Inherited Metabolic Diseases of the Liver. Yale J Biol Med. 2017 Dec 19;90(4):553-566.Chernikov IV, Vlassov VV, Chernolovskaya EL. Current Development of siRNA Bioconjugates: From Research to the Clinic. Front Pharmacol. 2019 Apr 26;10:444. doi: 10.3389/fphar.2019.00444.Chernikov IV, Vlassov VV, Chernolovskaya EL. Current Development of siRNA Bioconjugates: From Research to the Clinic. Front Pharmacol. 2019 Apr 26;10:444. doi: 10.3389/fphar.2019.00444.Buck AH. Cells choose their words wisely. Cell. 2022 Mar 31;185(7):1114-1116. doi: 10.1016/j.cell.2022.03.010.Buck AH. Cells choose their words wisely. Cell. 2022 Mar 31;185(7):1114-1116. doi: 10.1016/j.cell.2022.03.010.Urits I, Swanson D, Swett MC, Patel A, Berardino K, Amgalan A, Berger AA, Kassem H, Kaye AD, Viswanath O. A Review of Patisiran (ONPATTRO ®) for the Treatment of Polyneuropathy in People with Hereditary Transthyretin Amyloidosis. Neurol Ther. 2020 Dec;9(2):301-315. doi: 10.1007/s40120-020-00208-1.Urits I, Swanson D, Swett MC, Patel A, Berardino K, Amgalan A, Berger AA, Kassem H, Kaye AD, Viswanath O. A Review of Patisiran (ONPATTRO ®) for the Treatment of Polyneuropathy in People with Hereditary Transthyretin Amyloidosis. Neurol Ther. 2020 Dec;9(2):301-315. doi: 10.1007/s40120-020-00208-1.Habtemariam BA, Karsten V, Attarwala H, Goel V, Melch M, Clausen VA, Garg P, Vaishnaw AK, Sweetser MT, Robbie GJ, Vest J. Single- Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine- Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021 Feb;109(2):372-382. doi: 10.1002/cpt.1974.Habtemariam BA, Karsten V, Attarwala H, Goel V, Melch M, Clausen VA, Garg P, Vaishnaw AK, Sweetser MT, Robbie GJ, Vest J. Single- Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine- Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021 Feb;109(2):372-382. doi: 10.1002/cpt.1974.Syed YY. Givosiran: A Review in Acute Hepatic Porphyria. Drugs. 2021 May;81(7):841-848. doi: 10.1007/s40265-021-01511-3.Syed YY. Givosiran: A Review in Acute Hepatic Porphyria. Drugs. 2021 May;81(7):841-848. doi: 10.1007/s40265-021-01511-3.Forbes TA, Brown BD, Lai C. Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria. Br J Clin Pharmacol. 2022 Jun;88(6):2525-2538. doi: 10.1111/bcp.14925.Forbes TA, Brown BD, Lai C. Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria. Br J Clin Pharmacol. 2022 Jun;88(6):2525-2538. doi: 10.1111/bcp.14925.Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol. 2021 Jul;189:114432. doi: 10.1016/j.bcp.2021.114432.Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol. 2021 Jul;189:114432. doi: 10.1016/j.bcp.2021.114432.

The authors declare that there are no conflicts of interest present.