Silent players, loud impact: unveiling the therapeutic potentials of LncRNAs

Abstract

Long non-coding RNAs (lncRNAs) are a class of RNA transcripts that are long (i.e., more than 200 nucleotides) and not translated into proteins. They have recently emerged as potential treatment targets for numerous disorders due to their involvement in multiple cellular functions such as gene regulation, epigenetic modulation, and chromatin organization. This review highlights the current state of lncRNA-based therapeutics, the potential of lncRNAs as drug targets for treating human diseases, the various strategies and types of RNA-based therapeutics, and the complications of developing lncRNA-based drugs. We conclude that lncRNA-based therapeutics represent a promising class of drugs that can potentially treat various human diseases and that further research is needed to fully realize their therapeutic potential.

Keywords

Long non-coding RNA / RNA-based therapeutics / LncRNA-based drugs / small interfering RNAs / short hairpin RNAs / microRNAs

References

[1] Malik B.Long noncoding RNAs in prostate cancer: overview and clinical implications.Asian J Androl2016;18:568-74 PMCID:PMC4955180

[2] Shi T,Cao Y.Long noncoding RNAs as novel biomarkers have a promising future in cancer diagnostics.Dis Markers2016;2016:9085195 PMCID:PMC4842029

[3] Jiang X,Hu M.Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells.J Neurosurg2016;124:129-36

[4] Ma L,Zhang Z.On the classification of long non-coding RNAs.RNA Biol2013;10:925-33 PMCID:PMC4111732

[5] Zhan L,Wei B.Long non-coding RNAs in ovarian cancer.J Exp Clin Cancer Res2018;37:120 PMCID:PMC6008930

[6] Xi J,Ma L.Long non-coding RNAs in glioma progression.Cancer Lett2018;419:203-9

[7] Yang M,Guo S,Zhu Y.Long non-coding RNA FLJ33360 participates in ovarian cancer progression by sponging miR-30b-3p.Onco Targets Ther2019;12:4469-80 PMCID:PMC6560195

[8] Shao M,Wang Y.Differentially expressed LncRNAs as potential prognostic biomarkers for glioblastoma.Cancer Genet2018;226-7:23-9

[9] Kiang KMY.Clinical significance of CRNDE transcript variants in glioblastoma multiforme.Noncoding RNA Res2017;2:119-21 PMCID:PMC6096424

[10] Ma Y,Dong D,Wang Y.Characterization of long non-coding RNAs to reveal potential prognostic biomarkers in hepatocellular carcinoma.Gene2018;663:148-56

[11] Zeng T,Zhou Y.Exploring long noncoding RNAs in glioblastoma: regulatory mechanisms and clinical potentials.Int J Genomics2018;2018:2895958 PMCID:PMC6079499

[12] Balas MM.Exploring the mechanisms behind long noncoding RNAs and cancer.Noncoding RNA Res2018;3:108-17 PMCID:PMC6114262

[13] Cabili MN,McClanahan PD.Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution.Genome Biol2015;16:20 PMCID:PMC4369099

[14] Duran R, Wei H, Kim DH, Wu JQ. Invited review: long non-coding RNAs: important regulators in the development, function and disorders of the central nervous system.Neuropathol Appl Neurobiol2019;45:538-56 PMCID:PMC6626588

[15] Bridges MC,Kourtidis A.LNCcation: lncRNA localization and function.J Cell Biol2021;220:e202009045 PMCID:PMC7816648

[16] Clark MB,Inostroza-Ponta M.Genome-wide analysis of long noncoding RNA stability.Genome Res2012;22:885-98 PMCID:PMC3337434

[17] Bresson SM,Hunter AC.Canonical Poly(A) polymerase activity promotes the decay of a wide variety of mammalian nuclear RNAs.PLoS Genet2015;11:e1005610 PMCID:PMC4618350

[18] Du Z,Hacisuleyman E.Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer.Nat Commun2016;7:10982 PMCID:PMC4796315

[19] Grelet S,Howley B.A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression.Nat Cell Biol2017;19:1105-15 PMCID:PMC5578890

[20] Lin A,Xing Z.The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.Nat Cell Biol2016;18:213-24 PMCID:PMC4791069

[21] Gong C.lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements.Nature2011;470:284-8 PMCID:PMC3073508

[22] Rackham O,Mercer TR,Mattick JS.Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins.RNA2011;17:2085-93 PMCID:PMC3222122

[23] Noh JH,Abdelmohsen K.HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP.Genes Dev2016;30:1224-39 PMCID:PMC4888842

[24] Kaewsapsak P,Mallard W,Ting AY.Live-cell mapping of organelle-associated RNAs via proximity biotinylation combined with protein-RNA crosslinking.Elife2017;6:e29224 PMCID:PMC5730372

[25] Fazal FM,Parker KR.Atlas of subcellular RNA localization revealed by APEX-Seq.Cell2019;178:473-90.e26 PMCID:PMC6786773

[26] Jiang C,Zhao Z.Identifying and functionally characterizing tissue-specific and ubiquitously expressed human lncRNAs.Oncotarget2016;7:7120-33 PMCID:PMC4872773

[27] Derrien T,Bussotti G.The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.Genome Res2012;22:1775-89 PMCID:PMC3431493

[28] Washietl S,Garber M.Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals.Genome Res2014;24:616-28 PMCID:PMC3975061

[29] Wu Z,Liu L.Regulation of lncRNA expression.Cell Mol Biol Lett2014;19:561-75 PMCID:PMC6275606

[30] Macrae TA,Ramalho-Santos M.Regulation, functions and transmission of bivalent chromatin during mammalian development.Nat Rev Mol Cell Biol2023;24:6-26

[31] Bernstein BE,Xie X.A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Cell2006;125:315-26

[32] Beck D,Skinner MK.Genome-wide CpG density and DNA methylation analysis method (MeDIP, RRBS, and WGBS) comparisons.Epigenetics2022;17:518-30 PMCID:PMC9067529

[33] Elango N.DNA methylation and structural and functional bimodality of vertebrate promoters.Mol Biol Evol2008;25:1602-8

[34] Song G,Zhu J.Integrated analysis of dysregulated lncRNA expression in fetal cardiac tissues with ventricular septal defect.PLoS One2013;8:e77492 PMCID:PMC3797806

[35] Wan G,Liu Y.A novel non-coding RNA lncRNA-JADE connects DNA damage signalling to histone H4 acetylation.EMBO J2013;32:2833-47 PMCID:PMC3817469

[36] Dinger ME,Mercer TR.Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.Genome Res2008;18:1433-45 PMCID:PMC2527704

[37] Braconi C,Valeri N.microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer.Oncogene2011;30:4750-6 PMCID:PMC4292930

[38] Wang J,Wu H.CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer.Nucleic Acids Res2010;38:5366-83 PMCID:PMC2938198

[39] Shi X,Wu Y.Post-transcriptional regulation of long noncoding RNAs in cancer.Tumour Biol2015;36:503-13

[40] Chiyomaru T,Saini S.Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells.J Biol Chem2014;289:12550-65 PMCID:PMC4007447

[41] Yoon JH,Kim J.Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination.Nat Commun2013;4:2939 PMCID:PMC4556280

[42] Han Y,Zhang H.Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long noncoding RNA MALAT1.FEBS Lett2013;587:3875-82

[43] Wilusz JE,Lu LY,Joshua-Tor L.A triple helix stabilizes the 3' ends of long noncoding RNAs that lack poly(A) tails.Genes Dev2012;26:2392-407 PMCID:PMC3489998

[44] Brown JA,Yario TA,Steitz JA.Formation of triple-helical structures by the 3'-end sequences of MALAT1 and MENβ noncoding RNAs.Proc Natl Acad Sci USA2012;109:19202-7 PMCID:PMC3511071

[45] Cantara WA,Rozenski J.The RNA Modification Database, RNAMDB: 2011 update.Nucleic Acids Res2011;39:D195-201 PMCID:PMC3013656

[46] Yang Y,Jin Y.ADAR-mediated RNA editing in non-coding RNA sequences.Sci China Life Sci2013;56:944-52

[47] Califf RM.Biomarker definitions and their applications.Exp Biol Med2018;243:213-21 PMCID:PMC5813875

[48] Yang Y,Su X,Bai W.MSCs-derived exosomes and neuroinflammation, neurogenesis and therapy of traumatic brain injury.Front Cell Neurosci2017;11:55 PMCID:PMC5329010

[49] Kim DK,An SY,Bartosh TJ.Chromatographically isolated CD63⁺CD81⁺ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI.Proc Natl Acad Sci USA2016;113:170-5 PMCID:PMC4711859

[50] Shi Y,Nomi A,Zhang B.Mesenchymal stem cell-derived extracellular vesicles: a new impetus of promoting angiogenesis in tissue regeneration.Cytotherapy2019;21:497-508

[51] Roura S,Munizaga-Larroudé M.Potential of extracellular vesicle-associated TSG-6 from adipose mesenchymal stromal cells in traumatic brain injury.Int J Mol Sci2020;21:6761 PMCID:PMC7554813

[52] Wang CF,Weng WJ.Alteration in long non-coding RNA expression after traumatic brain injury in rats.J Neurotrauma2017;34:2100-8

[53] Zhong J,Cheng C.Altered expression of long non-coding RNA and mRNA in mouse cortex after traumatic brain injury.Brain Res2016;1646:589-600

[54] Yang LX,Zhu J,Wang YH.Expression signatures of long non-coding RNA and mRNA in human traumatic brain injury.Neural Regen Res2019;14:632-41 PMCID:PMC6352599

[55] Shen H,You Z,Zhao Y.Advances in biomaterial-based spinal cord injury repair.Adv Funct Mater2022;32:2110628

[56] Badhiwala JH,Fehlings MG.Global burden of traumatic brain and spinal cord injury.Lancet Neurol2019;18:24-5

[57] Hatch BB,Therneau TM,Payne JM.Factors predictive of survival and estimated years of life lost in the decade following nontraumatic and traumatic spinal cord injury.Spinal Cord2017;55:540-4

[58] Ramer LM,Bradbury EJ.Restoring function after spinal cord injury: towards clinical translation of experimental strategies.Lancet Neurol2014;13:1241-56

[59] Wang J,Cao F,Zhang Y.Down regulation of lncSCIR1 after spinal cord contusion injury in rat.Brain Res2015;1624:314-20

[60] Zhou H,Kang Y.Investigation of candidate long noncoding RNAs and messenger RNAs in the immediate phase of spinal cord injury based on gene expression profiles.Gene2018;661:119-25

[61] Wang W,Tang S.Identification of noncoding RNA expression profiles and regulatory interaction networks following traumatic spinal cord injury by sequence analysis.Aging2019;11:2352-68 PMCID:PMC6520015

[62] Moonga J.A systematic literature review on nurses’ and health care support workers’ experiences of caring for people with dementia on orthopaedic wards.J Clin Nurs2016;25:1789-804

[63] Näslund J,Mohs R.Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.JAMA2000;283:1571-7

[64] Vassar R.The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease.Alzheimers Res Ther2011;3:20 PMCID:PMC3226309

[65] Riva P,Venturin M.The long non-coding RNAs in neurodegenerative diseases: novel mechanisms of pathogenesis.Curr Alzheimer Res2016;13:1219-31

[66] Airavaara M,Doyle ME,Troncoso JC.Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease.J Biol Chem2011;286:45093-102 PMCID:PMC3247946

[67] Massone S,Fiorino G.17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease.Neurobiol Dis2011;41:308-17

[68] Parenti R,Torrisi A.A natural antisense transcript against Rad18, specifically expressed in neurons and upregulated during beta-amyloid-induced apoptosis.Eur J Neurosci2007;26:2444-57

[69] Mus E,Tiedge H.Dendritic BC200 RNA in aging and in Alzheimer's disease.Proc Natl Acad Sci USA2007;104:10679-84 PMCID:PMC1965572

[70] Ciarlo E,Penna I.An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples.Dis Model Mech2013;6:424-33 PMCID:PMC3597024

[71] Massone S,Vella S.NDM29, a RNA polymerase III-dependent non coding RNA, promotes amyloidogenic processing of APP and amyloid β secretion.Biochim Biophys Acta2012;1823:1170-7

[72] Gu C,Wu R.Long noncoding RNA EBF3-AS promotes neuron apoptosis in Alzheimer's disease.DNA Cell Biol2018;37:220-6

[73] Ferreira JJ,Duarte GS.An MDS evidence-based review on treatments for Huntington's disease.Mov Disord2022;37:25-35

[74] Lee M,Im W.Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington's disease in vitro model.Eur J Neurosci2016;44:2114-9

[75] McColgan P.Huntington's disease: a clinical review.Eur J Neurol2018;25:24-34

[76] Chung DW,Yu L.A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression.Hum Mol Genet2011;20:3467-77 PMCID:PMC3153309

[77] Sunwoo JS,Im W.Altered expression of the long noncoding RNA NEAT1 in Huntington's disease.Mol Neurobiol2017;54:1577-86

[78] Koistinen H,Hollenberg MD.The roles of proteases in prostate cancer.IUBMB Life2023;75:493-513 PMCID:PMC10159896

[79] Chakravarty D,Nair SS.The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer.Nat Commun2014;5:5383

[80] Yuan S,Zhang Y.LncRNA SSTR5-AS1 as a prognostic marker promotes cell proliferation and epithelial-to-mesenchymal transition in prostate cancer.Crit Rev Eukaryot Gene Expr2023;33:1-12

[81] Siegel RL,Fuchs HE.Cancer statistics, 2022.CA Cancer J Clin2022;72:7-33

[82] Sideris N,Bayraktar S,Castellano L.LncRNAs in breast cancer: a link to future approaches.Cancer Gene Ther2022;29:1866-77 PMCID:PMC9750866

[83] Sang Y,Li S.LncRNA PANDAR regulates the G1/S transition of breast cancer cells by suppressing p16(INK4A) expression.Sci Rep2016;6:22366 PMCID:PMC4772134

[84] Zhang J,Wu H.The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.Cell Death Dis2019;10:599 PMCID:PMC6687715

[85] Li H,Fan J.Identification of cardiac long non-coding RNA profile in human dilated cardiomyopathy.Cardiovasc Res2018;114:747-58

[86] Zhang X,Liu J.Overexpression of cytosolic long noncoding RNA cytb protects against pressure-overload-induced heart failure via sponging microRNA-103-3p.Mol Ther Nucleic Acids2022;27:1127-45 PMCID:PMC8881631

[87] Xie R,Wen J.LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway.Mol Ther Nucleic Acids2023;32:689-703 PMCID:PMC10199406

[88] Fan J,Xie R.LncRNA ZNF593-AS alleviates contractile dysfunction in dilated cardiomyopathy.Circ Res2021;128:1708-23

[89] Zhong J,Huang Z.The long non-coding RNA Neat1 is an important mediator of the therapeutic effect of bexarotene on traumatic brain injury in mice.Brain Behav Immun2017;65:183-94

[90] Patel NA,Lee JY.Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury.J Neuroinflamm2018;15:204 PMCID:PMC6044101

[91] Harris L,Piper M.Insights into the biology and therapeutic applications of neural stem cells.Stem Cells Int2016;2016:9745315 PMCID:PMC4812498

[92] Zheng J,Liu Y,Zhu Y. Long nonding RNA UCA1 regulates neural stem cell differentiation by controlling miR-1/Hes1 expression. Am J Transl Res 2017;9:3696-704. Available from: https://europepmc.org/article/MED/28861160 [Last accessed on 1 Apr 2024]

[93] Liu Y,Jiang A.Hydrogen sulfide upregulated lncRNA CasC7 to reduce neuronal cell apoptosis in spinal cord ischemia-reperfusion injury rat.Biomed Pharmacother2018;98:856-62

[94] Agrawal N,Mohmmed A,Bhatnagar RK.RNA interference: biology, mechanism, and applications.Microbiol Mol Biol Rev2003;67:657-85 PMCID:PMC309050

[95] Faghihi MA,Khalil AM.Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.Nat Med2008;14:723-30 PMCID:PMC2826895

[96] Johnson R.Long non-coding RNAs in Huntington's disease neurodegeneration.Neurobiol Dis2012;46:245-54

[97] Ksiazek-Winiarek DJ,Glabinski A.Neural plasticity in multiple sclerosis: the functional and molecular background.Neural Plast2015;2015:307175 PMCID:PMC4503575

[98] Baquet ZC,Jones KR.Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor.J Neurosci2004;24:4250-8 PMCID:PMC6729276

[99] Zuccato C,Crotti A.Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.Nat Genet2003;35:76-83

[100] Ghafouri-Fard S,Taheri M.A concise review on the role of BDNF-AS in human disorders.Biomed Pharmacother2021;142:112051

[101] Yin X,Ge R.Long non-coding RNA DNMBP-AS1 promotes prostate cancer development by regulating LCLAT1.Syst Biol Reprod Med2023;69:142-52

[102] Zhang W,Xu Q,Zhu H.Long non-coding RNA MIR22HG suppresses cell proliferation and promotes apoptosis in prostate cancer cells by sponging microRNA-9-3p.Bioengineered2022;13:13108-17 PMCID:PMC9275890

[103] Ren Y,Xu YQ.Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion.Mol Cancer2018;17:5 PMCID:PMC5765658

[104] Khorkova O.Oligonucleotide therapies for disorders of the nervous system.Nat Biotechnol2017;35:249-63 PMCID:PMC6043900

[105] Zhu Y,Wang X.RNA-based therapeutics: an overview and prospectus.Cell Death Dis2022;13:644 PMCID:PMC9308039

[106] Winkle M,Fabbri M.Noncoding RNA therapeutics - challenges and potential solutions.Nat Rev Drug Discov2021;20:629-51 PMCID:PMC8212082

[107] Chi X,Papoian T.Safety of antisense oligonucleotide and siRNA-based therapeutics.Drug Discov Today2017;22:823-33

[108] Migliorati JM,Liu A.Absorption, distribution, metabolism, and excretion of US food and drug administration-approved antisense oligonucleotide drugs.Drug Metab Dispos2022;50:888-97

[109] Germain ND,Sarmiere PD.RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases.Mol Aspects Med2023;91:101148

[110] Sheng P,Xie M.Short hairpin RNAs for strand-specific small interfering RNA production.Front Bioeng Biotechnol2020;8:940 PMCID:PMC7427337

[111] Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age.EMBO Mol Med2014;6:851-64 PMCID:PMC4119351

[112] Lima JF,Figueiredo C,Azevedo NF.Anti-miRNA oligonucleotides: a comprehensive guide for design.RNA Biol2018;15:338-52 PMCID:PMC5927725

[113] Kluiver J,Smigielska-Czepiel K,Kroesen BJ.Generation of miRNA sponge constructs.Methods2012;58:113-7

[114] Chang S.Construction of multi-potent microRNA sponge and its functional evaluation. In: Wu W, editor. MicroRNA and cancer. New York: Springer; 2018. pp. 201-9.

[115] Jung J,Choi YS.Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge.Oncotarget2015;6:20370-87 PMCID:PMC4653011

[116] Das S,Dunkerly-Eyring B.Divergent effects of miR-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microRNA targets.J Am Heart Assoc2017;6:e004694 PMCID:PMC5524005

[117] Wang Z.The Principles of MiRNA-masking antisense oligonucleotides technology. In: Wu W, editor. MicroRNA and cancer. Totowa: Humana Press; 2011. pp. 43-9.

[118] Gilot D,Bachelot L.A non-coding function of TYRP1 mRNA promotes melanoma growth.Nat Cell Biol2017;19:1348-57

[119] Almarghalani DA,Ali M.Small interfering RNAs based therapies for intracerebral hemorrhage: challenges and progress in drug delivery systems.Neural Regen Res2022;17:1717-25 PMCID:PMC8820693

[120] Friedrich M.Therapeutic siRNA: state-of-the-art and future perspectives.BioDrugs2022;36:549-71 PMCID:PMC9396607

[121] Statello L,Chen LL.Gene regulation by long non-coding RNAs and its biological functions.Nat Rev Mol Cell Biol2021;22:96-118

[122] Modarresi F,Lopez-Toledano MA.Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation.Nat Biotechnol2012;30:453-9 PMCID:PMC4144683

[123] Lee D,Kaku HN.Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome.Elife2023;12:e81892

[124] de Smet MD, Meenken CJ, van den Horn GJ. Fomivirsen - a phosphorothioate oligonucleotide for the treatment of CMV retinitis.Ocul Immunol Inflamm1999;7:189-98

[125] Parham JS.Mipomersen and its use in familial hypercholesterolemia.Expert Opin Pharmaco2019;20:127-31 PMCID:PMC6438693

[126] Scott LJ.Givosiran: first approval.Drugs2020;80:335-9

[127] Gebert LF,Crivelli SE,Stoffel M.Miravirsen (SPC3649) can inhibit the biogenesis of miR-122.Nucleic Acids Res2014;42:609-21 PMCID:PMC3874169

[128] Gallant-Behm CL,Lynch JM.A MicroRNA-29 mimic (Remlarsen) represses extracellular matrix expression and fibroplasia in the skin.J Invest Dermatol2019;139:1073-81

[129] Regulus Therapeutics I. RG-125 (AZD4076), a microRNA therapeutic targeting microRNA-103/107 for the treatment of NASH in patients with type 2 diabetes/pre-diabetes, selected as clinical candidate by AstraZeneca. 2015. Available from: https://www.prnewswire.com/news-releases/rg-125-azd4076-a-microrna-therapeutic-targeting-microrna-103107-for-the-treatment-of-nash-in-patients-with-type-2-diabetespre-diabetes-selected-as-clinical-candidate-by-astrazeneca-300062261.html [Last accessed on 1 Apr 2024]

[130] Bouchie A.First microRNA mimic enters clinic.Nat Biotechnol2013;31:577

[131] Siddiqui MA.Pegaptanib: in exudative age-related macular degeneration.Drugs2005;65:1571-7; discussion 1578-9

[132] Goodkey K,Maruyama R.Nusinersen in the treatment of spinal muscular atrophy. In: Yokota T, Maruyama R, editors. Exon skipping and inclusion therapies. New York: Springer; 2018. pp. 69-76.

[133] Hoy SM.Patisiran: first global approval.Drugs2018;78:1625-31

[134] Scott LJ.Lumasiran: first approval.Drugs2021;81:277-82

[135] Bravo-Hernandez M,Navarro MR.Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.Nat Med2020;26:118-30 PMCID:PMC8171115

[136] Arun G,Spector DL.Therapeutic targeting of long non-coding RNAs in cancer.Trends Mol Med2018;24:257-77 PMCID:PMC5840027

[137] Matsui M.Non-coding RNAs as drug targets.Nat Rev Drug Discov2017;16:167-79 PMCID:PMC5831170

[138] Lennox KA.Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides.Nucleic Acids Res2016;44:863-77 PMCID:PMC4737147

[139] Gagnon KT,Chu Y,Corey DR.RNAi factors are present and active in human cell nuclei.Cell Rep2014;6:211-21 PMCID:PMC3916906

[140] Kumar H,Akira S.Pathogen recognition by the innate immune system.Int Rev Immunol2011;30:16-34

[141] Sioud M.Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2'-hydroxyl uridines in immune responses.Eur J Immunol2006;36:1222-30

[142] Barton GM.Toll-like receptor signaling pathways.Science2003;300:1524-5

[143] Hong DS,Borad M.Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.Br J Cancer2020;122:1630-7 PMCID:PMC7251107

[144] Beg MS,Sachdev J.Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.Invest New Drugs2017;35:180-8 PMCID:PMC5893501

[145] Pisano M,Sini MC,Tanda F.Targeting Bcl-2 protein in treatment of melanoma still requires further clarifications.Ann Oncol2008;19:2092-3 PMCID:PMC2733126

[146] Anderson EM,Ilsley D.Gene profiling study of G3139- and Bcl-2-targeting siRNAs identifies a unique G3139 molecular signature.Cancer Gene Ther2006;13:406-14

[147] Winkler J,Amartey J.Off-target effects related to the phosphorothioate modification of nucleic acids.ChemMedChem2010;5:1344-52

[148] Wen J.miR-122 regulates hepatic lipid metabolism and tumor suppression.J Clin Invest2012;122:2773-6 PMCID:PMC3408753

[149] Ui-Tei K,Nishi K,Saigo K.Thermodynamic stability and Watson-Crick base pairing in the seed duplex are major determinants of the efficiency of the siRNA-based off-target effect.Nucleic Acids Res2008;36:7100-9 PMCID:PMC2602766

[150] Grimm D,Jopling CL.Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways.Nature2006;441:537-41

[151] Khan AA,Miller ML,Leslie CS.Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs.Nat Biotechnol2009;27:549-55 PMCID:PMC2782465

[152] Hart M,Walch-Rueckheim B.Wrinkle in the plan: miR-34a-5p impacts chemokine signaling by modulating CXCL10/CXCL11/CXCR3-axis in CD4⁺, CD8⁺ T cells, and M1 macrophages.J Immunother Cancer2020;8:e001617 PMCID:PMC7684812

[153] LaCasse EC.Pulling the plug on a cancer cell by eliminating XIAP with AEG35156.Cancer Lett2013;332:215-24

[154] Fazaeli H,Ghasemian F,Sheykhhasan M.The emerging role of LncRNA FENDRR in multiple cancers: a review.Curr Mol Med2023;23:606-29

[155] da Silva AMG, Cruz MS, de Souza KSC, Silbiger VN. Long non-coding RNA and circular RNA: new perspectives for molecular pathophysiology of atrial fibrillation.Mol Biol Rep2023;50:2835-45

[156] Loganathan T.Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets.Funct Integr Genomics2023;23:33 PMCID:PMC9838419

[157] Jiapaer Z,Yang X.Extracellular non-coding RNAs in cardiovascular diseases.Pharmaceutics2023;15:155 PMCID:PMC9865796

[158] Dong B,Zhang W.IncRNA EPB41L4A-AS1 mitigates the proliferation of non-small-cell lung cancer cells through the miR-105-5p/GIMAP6 axis.Crit Rev Eukaryot Gene Expr2023;33:27-40

[159] Hu W,Lodish HF.Regulation of mammalian cell differentiation by long non-coding RNAs.EMBO Rep2012;13:971-83 PMCID:PMC3492712