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2000
Volume 31, Issue 22
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Rheumatoid Arthritis (RA) is a chronic autoimmune disease that prominently affects the joints of the body, including one or more types, such as wrists, knees, fingers, and toes. This condition is characterized by specific auto-immune responses, ., inflammation, swelling, stiffness, and pain in the body's joints. This results in partial or complete immobility. Several treatment options are available in the pharmaceutical market, commonly immunosuppressants, anti-inflammatory drugs, corticosteroids, anti-antibody drugs, . However, such drug treatments provide only symptomatic relief and lack long-term therapeutic efficacy. Thus, there is a need to develop an alternative treatment option that potentially can cure this disease. Recently, researchers have shifted their focus to targeting the root cause involved in the pathogenesis of RA by designing nucleic-acid-based molecules. With this objective, we have provided this review in which we have explored the nucleic acid-based techniques used to treat RA. Various molecular and genetic methods, including antisense oligonucleotides, small interfering RNA (siRNA), CRISPR-Cas9 gene editing, RNA-based vaccines, microRNA (miRNA) therapeutics, and epigenetic modifications are used to target the mechanisms underlying RA pathogenesis. Through the extensive evaluation of clinical and preclinical studies, we reported nucleic acid-based therapy's clinical efficacy, safety, and therapeutic benefits. In addition, this study states the associated pharmacokinetic challenges followed by approaches to overcome them. Nucleic acid-based therapies are susceptible to degradation by nucleases in the body and are not efficiently absorbed due to their considerable molecular weight. Specialized carriers like nanoparticles are employed for their effective delivery. Nucleic acid-based therapies hold immense potential for achieving more effective, less toxic, and patient-centric management of RA, offering hope for improved outcomes and an enhanced quality of life for individuals living with this challenging autoimmune condition.

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References

  1. RaduA.F. BungauS.G. Management of rheumatoid arthritis: An overview.Cells20211011285710.3390/cells1011285734831081
    [Google Scholar]
  2. SchererHU HäuplT BurmesterGR The etiology of rheumatoid arthritis.J Autoimmun.202011010240010.1016/j.jaut.2019.102400
    [Google Scholar]
  3. ChaudharyA. VinayP. Rheumatoid arthritis: Etiology, treatment and animal models.J. Drug Deliv. Ther.202010529029810.22270/jddt.v10i5‑s.4357
    [Google Scholar]
  4. McInnesI.B. SchettG. Pathogenetic insights from the treatment of rheumatoid arthritis.Lancet2017389100862328233710.1016/S0140‑6736(17)31472‑128612747
    [Google Scholar]
  5. MarianiF.M. MartelliI. PistoneF. ChericoniE. PuxedduI. AlunnoA. Pathogenesis of rheumatoid arthritis: One year in review 2023.Clin. Exp. Rheumatol.20234191725173410.55563/clinexprheumatol/sgjk6e37497721
    [Google Scholar]
  6. DingQ. HuW. WangR. YangQ. ZhuM. LiM. CaiJ. RoseP. MaoJ. ZhuY.Z. Signaling pathways in rheumatoid arthritis: Implications for targeted therapy.Signal Transduct. Target. Ther.2023816810.1038/s41392‑023‑01331‑936797236
    [Google Scholar]
  7. TestaD. CalvacchiS. PetrelliF. GianniniD. BiliaS. AlunnoA. PuxedduI. One year in review 2021: Pathogenesis of rheumatoid arthritis.Clin. Exp. Rheumatol.202139344545210.55563/clinexprheumatol/j1l5l334018918
    [Google Scholar]
  8. CroiaC. BursiR. SuteraD. PetrelliF. AlunnoA. PuxedduI. One year in review 2019: Pathogenesis of rheumatoid arthritis.Clin. Exp. Rheumatol.201937334735731111823
    [Google Scholar]
  9. SparksJA Rheumatoid arthritis.Ann Intern Med20191701ITC1ITC1610.7326/AITC201901010
    [Google Scholar]
  10. AbbasiM. MousaviM.J. JamalzehiS. AlimohammadiR. BezvanM.H. MohammadiH. AslaniS. Strategies toward rheumatoid arthritis therapy; The old and the new.J. Cell. Physiol.20192347100181003110.1002/jcp.2786030536757
    [Google Scholar]
  11. BullockJ. RizviS.A.A. SalehA.M. AhmedS.S. DoD.P. AnsariR.A. AhmedJ. Rheumatoid arthritis: A brief overview of the treatment.Med. Princ. Pract.201827650150710.1159/00049339030173215
    [Google Scholar]
  12. LittlejohnEA MonradSU Early diagnosis and treatment of rheumatoid arthritis.Prim Care201845223725510.1016/j.pop.2018.02.010
    [Google Scholar]
  13. LinY.J. AnzagheM. SchülkeS. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis.Cells20209488010.3390/cells904088032260219
    [Google Scholar]
  14. Del Grossi MouraM. Cruz LopesL. SilvaM.T. Barberato-FilhoS. MottaR.H.L. BergamaschiC.C. Use of steroid and nonsteroidal anti-inflammatories in the treatment of rheumatoid arthritis.Medicine20189741e1265810.1097/MD.000000000001265830313057
    [Google Scholar]
  15. ChasovV. GaneevaI. ZmievskayaE. DavletshinD. GilyazovaE. ValiullinaA. BulatovE. Cell-based therapy and genome editing as emerging therapeutic approaches to treat rheumatoid arthritis.Cells20241315128210.3390/cells1315128239120313
    [Google Scholar]
  16. WengY. HuangQ. LiC. YangY. WangX. YuJ. HuangY. LiangX.J. Improved nucleic acid therapy with advanced nanoscale biotechnology.Mol. Ther. Nucleic Acids20201958160110.1016/j.omtn.2019.12.00431927331
    [Google Scholar]
  17. SridharanK. GogtayN.J. Therapeutic nucleic acids: Current clinical status.Br. J. Clin. Pharmacol.201682365967210.1111/bcp.1298727111518
    [Google Scholar]
  18. GuptaA AndresenJL MananRS LangerR Nucleic acid delivery for therapeutic applications.Adv Drug Deliv Rev202117811383410.1016/j.addr.2021.113834
    [Google Scholar]
  19. NavarroG. PanJ. TorchilinV.P. Micelle-like nanoparticles as carriers for DNA and siRNA.Mol. Pharm.201512230131310.1021/mp500721325557580
    [Google Scholar]
  20. KanazawaT. Brain delivery of small interfering ribonucleic acid and drugs through intranasal administration with nano-sized polymer micelles.Med Devices20158576410.2147/MDER.S7085625610007
    [Google Scholar]
  21. AllegranziB. TartariE. PittetD. "Seconds save lives - clean your hands": The 5 may 2021 world health organization save lives: Clean your hands campaign.J Hosp Infect20211111310.1016/j.jhin.2021.03.001
    [Google Scholar]
  22. ChuW-M. GongX. YoonT. Activation of innate immunity by microbial nucleic acids.Int. J. Mol. Sci.2003222413360
    [Google Scholar]
  23. SteffensR.C. WagnerE. Directing the way-receptor and chemical targeting strategies for nucleic acid delivery.Pharm. Res.2023401477610.1007/s11095‑022‑03385‑w36109461
    [Google Scholar]
  24. Di FuscoD. DinalloV. MarafiniI. FigliuzziM.M. RomanoB. MonteleoneG. Antisense oligonucleotide: Basic concepts and therapeutic application in inflammatory bowel disease.Front. Pharmacol.20191030510.3389/fphar.2019.0030530983999
    [Google Scholar]
  25. BajanS. HutvagnerG. RNA-based therapeutics: From antisense oligonucleotides to miRNAs.Cells20209113710.3390/cells901013731936122
    [Google Scholar]
  26. MakalishT.P. GolovkinI.O. OberemokV.V. LaikovaK.V. TemirovaZ.Z. SerdyukovaO.A. NovikovI.A. RosovskyiR.A. GordienkoA.I. ZyablitskayaE.Y. GafarovaE.A. YurchenkoK.A. FomochkinaI.I. KubyshkinA.V. Anti-rheumatic effect of antisense oligonucleotide cytos-11 targeting tnf-α expression.Int. J. Mol. Sci.2021223102210.3390/ijms2203102233498456
    [Google Scholar]
  27. WardwellPR ForstnerMB BaderRA Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models.Arthritis Res Ther20151731010.1186/s13075‑015‑0824‑x
    [Google Scholar]
  28. Alvarez-SalasL. Nucleic acids as therapeutic agents.Curr. Top. Med. Chem.20088151379140410.2174/15680260878614113318991725
    [Google Scholar]
  29. LaresMR RossiJJ OuelletDL RNAi and small interfering RNAs in human disease therapeutic applications.Trends Biotechnol2010281157057910.1016/j.tibtech.2010.07.009
    [Google Scholar]
  30. Zhang J, Chen B, Gan C, Sun H, Zhang J, Feng L. A comprehensive review of small interfering RNAs (siRNAs): Mechanism, therapeutic targets, and delivery strategies for cancer therapy. Int J Nanomed 2023; 18: 7605-3510.2147/IJN.S43603838106451
  31. HowardK.A. PaludanS.R. BehlkeM.A. BesenbacherF. DeleuranB. KjemsJ. Chitosan/siRNA nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model.Mol. Ther.200917116216810.1038/mt.2008.22018827803
    [Google Scholar]
  32. ChenJ. TangY. LiuY. DouY. Nucleic acid-based therapeutics for pulmonary diseases.AAPS PharmSciTech20181983670368010.1208/s12249‑018‑1183‑030338490
    [Google Scholar]
  33. DuanW LiH. Combination of NF-κB targeted siRNA and methotrexate in a hybrid nanocarrier towards the effective treatment in rheumatoid arthritis.J Nanobiotechnol20181615810.1186/s12951‑018‑0382‑x
    [Google Scholar]
  34. EvangelatosG FragoulisGE KoulouriV LambrouGI MicroRNAs in rheumatoid arthritis: From pathogenesis to clinical impact.Autoimmun Rev2019181110239110.1016/j.autrev.2019.102391
    [Google Scholar]
  35. LeeY. AhnC. HanJ. ChoiH. KimJ. YimJ. LeeJ. ProvostP. RådmarkO. KimS. KimV.N. The nuclear RNase III drosha initiates microRNA processing.Nature2003425695641541910.1038/nature0195714508493
    [Google Scholar]
  36. Castro-VillegasC. Pérez-SánchezC. EscuderoA. FilipescuI. VerduM. Ruiz-LimónP. AguirreM.A. Jiménez-GomezY. FontP. Rodriguez-ArizaA. PeinadoJ.R. Collantes-EstévezE. González-ConejeroR. MartinezC. BarbarrojaN. López-PedreraC. Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.Arthritis Res. Ther.20151714910.1186/s13075‑015‑0555‑z25860297
    [Google Scholar]
  37. HruskovaV. JandovaR. VernerovaL. MannH. PechaO. PrajzlerovaK. PavelkaK. VencovskyJ. FilkovaM. SenoltL. MicroRNA-125b: Association with disease activity and the treatment response of patients with early rheumatoid arthritis.Arthritis Res. Ther.201618112410.1186/s13075‑016‑1023‑027255643
    [Google Scholar]
  38. LeeM.H. ShinJ.I. YangJ.W. LeeK.H. ChaD.H. HongJ.B. ParkY. ChoiE. TizaouiK. KoyanagiA. JacobL. ParkS. KimJ.H. SmithL. Genome editing using CRISPR- Cas9 and autoimmune diseases: A comprehensive review.Int. J. Mol. Sci.2022233133710.3390/ijms2303133735163260
    [Google Scholar]
  39. IshinoY. KrupovicM. ForterreP. History of CRISPR-Cas from encounter with a mysterious repeated sequence to genome editing technology.J. Bacteriol.20182007e00580e1710.1128/JB.00580‑1729358495
    [Google Scholar]
  40. AsmamawM. ZawdieB. Mechanism and applications of CRISPR/Cas-9-mediated genome editing.Biologics20211535336134456559
    [Google Scholar]
  41. ShivaramanA. GuilzN Immunotherapy using CRISPR-Cas9 systems to treat rheumatoid arthritis with PTPN22 R620W mutations and target PD-1 and CD20.J High School Sci202261
    [Google Scholar]
  42. JingW. ZhangX. SunW. HouX. YaoZ. ZhuY. CRISPR/CAS9- mediated genome editing of miRNA-155 inhibits proinflammatory cytokine production by RAW264.BioMed Res. Int.201520151710.1155/2015/32604226697483
    [Google Scholar]
  43. LiM. FanY.N. ChenZ.Y. LuoY.L. WangY.C. LianZ.X. XuC-F. WangJ. Optimized nanoparticle-mediated delivery of CRISPR-Cas9 system for B cell intervention.Nano Res.201811126270628210.1007/s12274‑018‑2150‑5
    [Google Scholar]
  44. PiccirilloC. Prud’hommeG. Immune modulation by plasmid DNA-mediated cytokine gene transfer.Curr. Pharm. Des.200391839410.2174/138161203339240412570678
    [Google Scholar]
  45. JangD. LeeA.H. ShinH.Y. SongH.R. ParkJ.H. KangT.B. LeeS.R. YangS.H. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics.Int. J. Mol. Sci.2021225271910.3390/ijms2205271933800290
    [Google Scholar]
  46. SinghS. TiwaryN. SharmaN. BehlT. AntilA. AnwerM. RamniwasS. SachdevaM. ElossailyG. GulatiM. OhjaS. Integrating Nanotechnological advancements of disease-modifying anti-rheumatic drugs into rheumatoid arthritis management.Pharmaceuticals202417224810.3390/ph1702024838399463
    [Google Scholar]
  47. ZhangC. MaY. ZhangJ. KuoJ.C.T. ZhangZ. XieH. ZhuJ. LiuT. Modification of lipid-based nanoparticles: An efficient delivery system for nucleic acid-based immunotherapy.Molecules2022276194310.3390/molecules2706194335335310
    [Google Scholar]
  48. van den BergA.I.S. YunC.O. SchiffelersR.M. HenninkW.E. Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic.J. Control. Release202133112114110.1016/j.jconrel.2021.01.01433453339
    [Google Scholar]
  49. KumariA KaurA AggarwalG The emerging potential of siRNA nanotherapeutics in treatment of arthritis.Asian J Pharm Sci202318510084510.1016/j.ajps.2023.100845
    [Google Scholar]
  50. NsairatH. KhaterD. SayedU. OdehF. Al BawabA. AlshaerW. Liposomes: Structure, composition, types, and clinical applications.Heliyon202285e0939410.1016/j.heliyon.2022.e0939435600452
    [Google Scholar]
  51. LiZ ZhangL JiangK ZhangY LiuY HuG Biosafety assessment of delivery systems for clinical nucleic acid therapeutics.Biosaf Health20224210511710.1016/j.bsheal.2022.03.003
    [Google Scholar]
  52. Hald AlbertsenC. KulkarniJ.A. WitzigmannD. LindM. PeterssonK. SimonsenJ.B. The role of lipid components in lipid nanoparticles for vaccines and gene therapy.Adv. Drug Deliv. Rev.202218811441610.1016/j.addr.2022.11441635787388
    [Google Scholar]
  53. YanJ. ZhangH. LiG. SuJ. WeiY. XuC. Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design.Acta Pharm. Sin. B202414257960110.1016/j.apsb.2023.10.01238322344
    [Google Scholar]
  54. HejdankovaZ. VanekV. SedlakF. ProchazkaJ. DiederichsA. KereïcheS. NovotnaB. BudesinskyM. BirkusG. Grantz SaskovaK. CiglerP. Lipid nanoparticles for broad-spectrum nucleic acid delivery.Adv. Funct. Mater.20213147210139110.1002/adfm.202101391
    [Google Scholar]
  55. BaruaS. RamosJ. PottaT. TaylorD. HuangH.C. MontanezG. RegeK. Discovery of cationic polymers for non-viral gene delivery using combinatorial approaches.Comb Chem High Throughput Screen2011141090892410.2174/138620711797537076
    [Google Scholar]
  56. NiculescuA.G. BîrcăA.C. GrumezescuA.M. New applications of lipid and polymer-based nanoparticles for nucleic acids delivery.Pharmaceutics20211312205310.3390/pharmaceutics1312205334959335
    [Google Scholar]
  57. ZakeriA. KouhbananiM.A.J. BeheshtkhooN. BeigiV. MousaviS.M. HashemiS.A.R. Karimi ZadeA. AmaniA.M. SavardashtakiA. MirzaeiE. JahandidehS. MovahedpourA. Polyethylenimine-based nanocarriers in co-delivery of drug and gene: A developing horizon.Nano Rev. Exp.201891148849710.1080/20022727.2018.148849730410712
    [Google Scholar]
  58. ZhangX. LiuY. XiaoC. GuanY. GaoZ. HuangW. Research advances in nucleic acid delivery system for rheumatoid arthritis therapy.Pharmaceutics2023154123710.3390/pharmaceutics1504123737111722
    [Google Scholar]
  59. van der AaM.A.E.M. HuthU.S. HäfeleS.Y. SchubertR. OostingR.S. MastrobattistaE. HenninkW.E. Peschka-SüssR. KoningG.A. CrommelinD.J.A. Cellular uptake of cationic polymer-DNA complexes via caveolae plays a pivotal role in gene transfection in COS-7 cells.Pharm. Res.20072481590159810.1007/s11095‑007‑9287‑317385010
    [Google Scholar]
  60. LeeS. SonS. SongS. HaT. ChoiJ. Polyamidoamine (PAMAM) dendrimers modified with Cathepsin-B cleavable oligopeptides for enhanced gene delivery.Polymers20179622410.3390/polym906022430970901
    [Google Scholar]
  61. SukJS XuQ KimN HanesJ EnsignLM PEGylation as a strategy for improving nanoparticle-based drug and gene delivery.Adv Drug Deliv Rev201699Pt A285110.1016/j.addr.2015.09.012
    [Google Scholar]
  62. Di GioiaS. ConeseM. Polyethylenimine-mediated gene delivery to the lung and therapeutic applications.Drug Des. Devel. Ther.2009216318819920904
    [Google Scholar]
  63. KaurJ. MishraV. SinghS.K. GulatiM. KapoorB. ChellappanD.K. GuptaG. DurejaH. AnandK. DuaK. KhatikG.L. GowthamarajanK. Harnessing amphiphilic polymeric micelles for diagnostic and therapeutic applications: Breakthroughs and bottlenecks.J. Control. Release2021334649510.1016/j.jconrel.2021.04.01433887283
    [Google Scholar]
  64. DesaiN. RanaD. SalaveS. GuptaR. PatelP. KarunakaranB. SharmaA. GiriJ. BenivalD. KommineniN. Chitosan: A potential biopolymer in drug delivery and biomedical applications.Pharmaceutics2023154131310.3390/pharmaceutics1504131337111795
    [Google Scholar]
  65. ChourasiaM.K. JainS.K. Polysaccharides for colon targeted drug delivery.Drug Deliv.200411212914810.1080/1071754049028077815200012
    [Google Scholar]
  66. RafteryR. O’BrienF. CryanS.A. Chitosan for gene delivery and orthopedic tissue engineering applications.Molecules20131855611564710.3390/molecules1805561123676471
    [Google Scholar]
  67. KarayianniM. SentoukasT. SkandalisA. PippaN. PispasS. Chitosan-based nanoparticles for nucleic acid delivery: Technological aspects, applications, and future perspectives.Pharmaceutics2023157184910.3390/pharmaceutics1507184937514036
    [Google Scholar]
  68. HanH. XingJ. ChenW. JiaJ. LiQ. Fluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats.Nat. Commun.202314194410.1038/s41467‑023‑36625‑736805456
    [Google Scholar]
  69. ZhangJ. LiM. WangM. XuH. WangZ. LiY. DingB. GaoJ. Effects of the surface charge of polyamidoamine dendrimers on cellular exocytosis and the exocytosis mechanism in multidrug-resistant breast cancer cells.J. Nanobiotechnology202119113510.1186/s12951‑021‑00881‑w33980270
    [Google Scholar]
  70. ChangP.K.C. PrestidgeC.A. BremmellK.E. PAMAM versus PEI complexation for siRNA delivery: Interaction with model lipid membranes and cellular uptake.Pharm. Res.20223961151116310.1007/s11095‑022‑03229‑735318566
    [Google Scholar]
  71. LeeS.J. LeeA. HwangS.R. ParkJ.S. JangJ. HuhM.S. JoD.G. YoonS.Y. ByunY. KimS.H. KwonI.C. YounI. KimK. TNF-α gene silencing using polymerized siRNA/thiolated glycol chitosan nanoparticles for rheumatoid arthritis.Mol. Ther.201422239740810.1038/mt.2013.24524145554
    [Google Scholar]
  72. KhouryM. Louis-PlenceP. EscriouV. NoelD. LargeauC. CantosC. SchermanD. JorgensenC. ApparaillyF. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor α in experimental arthritis.Arthritis Rheum.20065461867187710.1002/art.2187616729293
    [Google Scholar]
  73. JainS. AmijiM. Tuftsin-modified alginate nanoparticles as a noncondensing macrophage-targeted DNA delivery system.Biomacromolecules20121341074108510.1021/bm201799322385328
    [Google Scholar]
  74. YinN. TanX. LiuH. HeF. DingN. GouJ. YinT. HeH. ZhangY. TangX. A novel indomethacin/methotrexate/MMP-9 siRNA in situ hydrogel with dual effects of anti-inflammatory activity and reversal of cartilage disruption for the synergistic treatment of rheumatoid arthritis.Nanoscale202012158546856210.1039/D0NR00454E32243486
    [Google Scholar]
  75. JansenM.A.A. KlausenL.H. ThankiK. LyngsøJ. Skov PedersenJ. FranzykH. NielsenH.M. van EdenW. DongM. BroereF. FogedC. ZengX. Lipidoid-polymer hybrid nanoparticles loaded with TNF siRNA suppress inflammation after intra-articular administration in a murine experimental arthritis model.Eur. J. Pharm. Biopharm.2019142384810.1016/j.ejpb.2019.06.00931199978
    [Google Scholar]
  76. HaoF. LeeR.J. ZhongL. DongS. YangC. TengL. MengQ. LuJ. XieJ. TengL. Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy.Theranostics20199185282529710.7150/thno.3226831410215
    [Google Scholar]
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  • Article Type:
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Keyword(s): ASOs; CRISPR-CAS9; miRNA; pharmacology; Rheumatoid arthritis; siRNA
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