Exploring miRNA Inhibiting Therapeutic Strategies for Multiple Sclerosis: Insights from Experimental Autoimmune Encephalomyelitis Studies – A Traditional Review

Yıl 2025, Cilt: 15 Sayı: 3, 498 - 508, 24.09.2025

Doğa Koruyucu , Birsen Can Demirdöğen

https://doi.org/10.33631/sabd.1560606

Öz

Multiple sclerosis (MS) is a chronic inflammatory disease in which immune cells attack the central nervous system (CNS) and cause degeneration of the myelin sheath. Although disease-modifying therapies are commonly used in the treatment of MS, these therapies cannot fully prevent or reverse the course of neurological deterioration. Furthermore, the response of patients with MS to these drugs may vary from person to person and over time. Therefore, the demand for new and more effective treatments continues. MicroRNAs (miRNAs) have the potential to alter biological processes that lead to various diseases. Hence, dysregulated miRNA levels are thought to be associated with the pathogenesis of MS. Considering the regulatory role of miRNAs in both the CNS and immune response, many studies have proposed them as potential new therapeutic targets for MS in addition to being potential biomarkers. In this traditional review, the primary focus is on miRNA-based therapeutic approaches, followed by a compilation of studies that utilized miRNA therapy to inhibit upregulated miRNAs in the animal model of MS, known as Experimental Autoimmune Encephalomyelitis (EAE).

Anahtar Kelimeler

miRNA , multiple sclerosis , therapy , experimental autoimmune encephalomyelitis

Multipl Skleroz için miRNA İnhibisyonuna Yönelik Terapötik Stratejilerin Keşfi: Deneysel Otoimmün Ensefalomiyelit Çalışmalarından Elde Edilen Bulgular- Geleneksel Bir Derleme

Öz

Multipl skleroz (MS), bağışıklık hücrelerinin merkezi sinir sistemine (MSS) saldırarak miyelin kılıfın dejenerasyonuna yol açtığı kronik bir enflamatuvar hastalıktır. MS tedavisinde sıklıkla hastalığı modifiye edici tedaviler kullanılmakla birlikte, bu yaklaşımlar nörolojik bozulmanın seyrini tamamen durdurmakta veya geri çevirmekte yetersiz kalmaktadır. Ayrıca, MS'li bireylerin bu tedavilere verdiği yanıt hem kişiden kişiye hem de zaman içinde değişkenlik gösterebilmektedir. Bu nedenle, daha etkili ve hedefe yönelik yeni tedavi stratejilerine olan ihtiyaç devam etmektedir. MikroRNA'lar (miRNA'lar), çeşitli hastalıklara neden olan biyolojik süreçleri değiştirme potansiyeline sahip küçük düzenleyici RNA molekülleridir. MS patogenezinde düzensiz miRNA ekspresyonunun önemli bir rol oynadığı düşünülmektedir. miRNA'ların hem MSS hem de bağışıklık sistemindeki düzenleyici etkileri göz önünde bulundurulduğunda, birçok çalışma bu molekülleri yalnızca potansiyel biyobelirteçler olarak değil, aynı zamanda terapötik hedefler olarak da önermiştir. Bu geleneksel derlemede, öncelikle miRNA inhibisyonuna yönelik tedavi yaklaşımları ele alınmış; ardından, MS'in deneysel hayvan modeli olan deneysel otoimmün ensefalomiyelit (DOE) kapsamında, aşırı ifade edilen miRNA'ların terapötik inhibisyonunu değerlendiren çalışmalar derlenmiştir.

Anahtar Kelimeler

miRNA , multipl skleroz , tedavi , deneysel otoimmun ensefalomiyelit

Etik Beyan

Bu makale etik ilkelere uygun bir biçimde hazırlanmıştır.

Destekleyen Kurum

-

Teşekkür

-

Kaynakça

• Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev. 2010;9(5):A387-94. https://doi.org/10.1016/j.autrev.2009.11.010
• Atlasofms.org [Internet]. Multiple Sclerosis International Federation – Atlas of MS – 3rd Edition. [cited: 2023 Jun 15]. Available from: https://www.atlasofms.org/map/global/epidemiology/number-of-people-with-ms.
• Dobson R, Giovannoni G. Multiple sclerosis - a review. Eur J Neurol. 2019;26(1):27-40. https://doi.org/10.1111/ene.13819
• Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. https://doi.org/10.1038/s41572-018-0041-4
• Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011;9(3):409-16. https://doi.org/10.2174/157015911796557911
• Huang Q, Xiao B, Ma X, Qu M, Li Y, Nagarkatti P, et al. MicroRNAs associated with the pathogenesis of multiple sclerosis. J Neuroimmunol. 2016;295-296:148-61. https://doi.org/10.1016/j.jneuroim.2016.04.014
• Basak J, Majsterek I. miRNA-Dependent CD4+ T Cell Differentiation in the Pathogenesis of Multiple Sclerosis. Mult Scler Int. 2021;2021:8825588. https://doi.org/10.1155/2021/8825588
• Saridas F, Tezcan Unlu H, Cecener G, Egeli U, Sabour Takanlou M, Sabour Takanlou L, et al. The expression and prognostic value of miR-146a and miR-155 in Turkish patients with multiple sclerosis. Neurol Res. 2022;44(3):217-23. https://doi.org/10.1080/01616412.2021.1975221
• Eisele SJG. MicroRNAs as a possible biomarker in the treatment of multiple sclerosis. IBRO Neurosci Rep. 2022;13:492-499. https://doi.org/10.1016/j.ibneur.2022.11.001
• Duffy CP, McCoy CE. The Role of MicroRNAs in Repair Processes in Multiple Sclerosis. Cells. 2020;9(7):1711. https://doi.org/10.3390/cells9071711
• Constantinescu CS, Farooqi N, O'Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079-106. https://doi.org/10.1111/j.1476-5381.2011.01302.x
• Ho PTB, Clark IM, Le LTT. MicroRNA-Based Diagnosis and Therapy. Int J Mol Sci. 2022;23(13):7167. https://doi.org/10.3390/ijms23137167
• McDermott AM, Heneghan HM, Miller N, Kerin MJ. The therapeutic potential of microRNAs: disease modulators and drug targets. Pharm Res. 2011;28(12):3016-29. https://doi.org/10.1007/s11095-011-0550-2
• Rupaimoole R, Slack F. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203-22. https://doi.org/10.1038/nrd.2016.246
• Gebert LF, Rebhan MA, Crivelli SE, Denzler R, Stoffel M, Hall J. Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res. 2014;42(1):609-21. https://doi.org/10.1093/nar/gkt852
• Li Y, Li Y, Huang C. Chapter 5 - Circulating miRNAs increasing the risk of cancer. In: Chakrabarti DJ, Mitra DS, editors. Cancer and Noncoding RNAs. Boston: Academic Press;2018. p. 79-94.
• Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 2014;13(8):622-38. https://doi.org/10.1038/nrd4359
• Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res. 2016;7(2):68-74. https://doi.org/10.4103/2229-3485.179431
• Tarhriz V, Hosseini K, Abkhooie L, Lazartigues E. CircRNA-Based AntimiR Therapy: a Novel Approach to Hypertension Treatment. Non-coding RNA Res. 2025;13:94-108. https://doi.org/10.1016/j.ncrna.2025.05.001
• Davis S, Lollo B, Freier S, Esau C. Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res. 2006;34(8):2294-304. https://doi.org/10.1093/nar/gkl183
• Zhang Z, Xue Z, Liu Y, Liu H, Guo X, Li Y, et al. MicroRNA-181c promotes Th17 cell differentiation and mediates experimental autoimmune encephalomyelitis. Brain Behav Immun. 2018;70:305-14. https://doi.org/10.1016/j.bbi.2018.03.011
• Rao DD, Vorhies JS, Senzer N, Nemunaitis J. siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev. 2009;61(9):746-59. https://doi.org/10.1016/j.addr.2009.04.004
• Luck ME, Muljo SA, Collins CB. Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases. J Immunol. 2015;194(11):5047-52. https://doi.org/10.4049/jimmunol.1403146
• Momen-Heravi F, Bala S, Bukong T, Szabo G. Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine. 2014;10(7):1517-27. https://doi.org/10.1016/j.nano.2014.03.014
• Ghasemi N, Razavi S, Nikzad E. Multiple Sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J. 2017;19(1):1-10. https://doi.org/10.22074/cellj.2016.4867
• Gao Y, Han D, Feng J. MicroRNA in multiple sclerosis. Clinica Chimica Acta. 2021;516:92-9. https://doi.org/10.22074/cellj.2016.4867
• Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252-9. https://doi.org/10.1038/ni.1798
• O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33(4):607-19. https://doi.org/10.1016/j.immuni.2010.09.009
• Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol. 2011;187(5):2213-21. https://doi.org/10.4049/jimmunol.1003952
• Zhang J, Cheng Y, Cui W, Li M, Li B, Guo L. MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014;266(1-2):56-63. https://doi.org/10.1016/j.jneuroim.2013.09.019
• Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, Selmaj KW. MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc Natl Acad Sci U S A. 2012;109(20):E1248-57. https://doi.org/10.1073/pnas.1114325109
• Guan H, Fan D, Mrelashvili D, Hao H, Singh NP, Singh UP, et al. Micro RNA let‐7e is associated with the pathogenesis of experimental autoimmune encephalomyelitis. Eur J Immunol. 2013;43(1):104-14. https://doi.org/10.1002/eji.201242702
• Liu X, He F, Pang R, Zhao D, Qiu W, Shan K, et al. Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme. J Biol Chem. 2014;289(42):28971-86. https://doi.org/10.1074/jbc.M114.577429
• Wan C, Ping CY, Shang XY, Tian JT, Zhao SH, Li L, et al. MicroRNA 182 inhibits CD4+CD25+Foxp3+ Treg differentiation in experimental autoimmune encephalomyelitis. Clin Immunol. 2016;173:109-16. https://doi.org/10.1016/j.clim.2016.09.008
• Wan C, Bi W, Lin P, Zhang Y, Tian J, Fang S, et al. MicroRNA 182 promotes T helper 1 cell by repressing hypoxia induced factor 1 alpha in experimental autoimmune encephalomyelitis. Eur J Immunol. 2019;49(12):2184-94. https://doi.org/10.1002/eji.201948111
• Lecca D, Marangon D, Coppolino GT, Méndez AM, Finardi A, Costa GD, et al. MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis. Sci Rep. 2016;6:34503. https://doi.org/10.1038/srep34503
• Marangon D, Boda E, Parolisi R, Negri C, Giorgi C, Montarolo F, et al. In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination. Glia. 2020;68(10):2001-14. https://doi.org/10.1002/glia.23819
• Ibrahim HM, AlZahrani A, Hanieh H, Ahmed EA, Thirugnanasambantham K. MicroRNA-7188-5p and miR-7235 regulates Multiple sclerosis in an experimental mouse model. Mol Immunol. 2021;139:157-67. https://doi.org/10.1016/j.molimm.2021.07.002
• Fujiwara M, Raheja R, Garo LP, Ajay AK, Kadowaki-Saga R, Karandikar SH, et al. microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance. J Clin Invest. 2022;132(10):e155693. https://doi.org/10.1172/JCI155693
• Nakashima M, Ishikawa K, Fujiwara A, Shu K, Fukushima Y, Okamoto M, et al. miR-451a levels rather than human papillomavirus vaccine administration is associated with the severity of murine experimental autoimmune encephalomyelitis. Scientific Reports. 2021;11(1):9369. https://doi.org/10.1038/s41598-021-88842-z
• Zhu E, Wang X, Zheng B, Wang Q, Hao J, Chen S, et al. miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORγt and STAT3. J Immunol. 2014;192(12):5599-609. https://doi.org/10.4049/jimmunol.1303488
• Osorio-Querejeta I, Carregal-Romero S, Ayerdi-Izquierdo A, Mäger I, A NL, Wood M, et al. MiR-219a-5p enriched extracellular vesicles induce opc differentiation and eae improvement more efficiently than liposomes and polymeric nanoparticles. Pharmaceutics. 2020;12(2):186. https://doi.org/10.3390/pharmaceutics12020186
• Clinicaltrialsregister.eu [Internet] European Medicines Agency. [cited: 2024 April 20]. Available from: https://www.clinicaltrialsregister.eu/ctrsearch/search?query=micro%2BRNA.