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      Long non-coding RNAs: From disease code to drug role

      review-article
      , , ,
      Acta Pharmaceutica Sinica. B
      Elsevier
      LncRNAs, Targeted drug, Gene therapy, Small molecules, Delivery, ASncmtRNA, Translational medicine, Clinical trials, AD, Alzheimer's disease, ANRIL, antisense noncoding RNA gene at the INK4 locus, ASncmtRNA, antisense noncoding mitochondrial RNA, ASO, antisense oligonucleotide, BCAR4, breast cancer anti-estrogen resistance 4, BDNF-AS, brain-derived neurotrophic factor antisense, CASC9, cancer susceptibility candidate 9, CDK, cyclin dependent kinase 1, CHRF, cardiac hypertrophy related factor, CRISPR, clustered regularly interspaced short palindromic repeats, DACH1, dachshund homolog 1, DANCR, differentiation antagonizing non-protein coding RNA, DKD, diabetic kidney disease, DPF, diphenyl furan, EBF3-AS, early B cell factor 3-antisense, ENE, element for nuclear expression, Erbb4-IR, Erb-B2 receptor tyrosine kinase 4-immunoreactivity, FDA, U.S. Food and Drug Administration, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, GAS5, growth arrest specific 5, HISLA, HIF-1α-stabilizing long noncoding RNA, HOTAIR, HOX transcript antisense intergenic RNA, HULC, highly upregulated in liver cancer, lincRNA-p21, long intergenic noncoding RNA p21, LIPCAR, long intergenic noncoding RNA predicting cardiac remodeling, LNAs, locked nucleic acids, lncRNAs, long non-coding RNAs, MALAT1, metastasis associated lung adenocarcinoma transcript 1, MEG3, maternally expressed gene 3, MHRT, myosin heavy chain associated RNA transcripts, MM, multiple myeloma, mtlncRNA, mitochondrial long noncoding RNA, NEAT1, nuclear enriched abundant transcript 1, NKILA, NF-kappaB interacting lncRNA, Norad, non-coding RNA activated by DNA damage, NPs, nanoparticles, OIP5-AS1, opa-interacting protein 5 antisense transcript 1, PD, Parkinson's disease, PEG, polyethylene glycol, PNAs, peptide nucleic acids, pHLIP, pH-low insertion peptide, PTO, phosphorothioate, PVT1, plasmacytoma variant translocation 1, RGD, arginine-glycine-aspartic acid peptide, RISC, RNA-induced silencing complex, SALRNA1, senescence associated long non-coding RNA 1, sgRNA, single guide RNA, siRNAs, small interfering RNAs, SncmtRNA, sense noncoding mitochondrial RNA, SNHG1, small nucleolar RNA host gene 1, THRIL, TNF and HNRNPL related immunoregulatory, TncRNA, trophoblast-derived noncoding RNA, TTTY15, testis-specific transcript, Y-linked 15, TUG1, taurine-upregulated gene 1, TWIST1, twist family BHLH transcription factor 1, UCA1, urothelial carcinoma-associated 1, UTF1, undifferentiated transcription factor 1, XIST, X-inactive specific transcript

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          Abstract

          Enormous studies have corroborated that long non-coding RNAs (lncRNAs) extensively participate in crucial physiological processes such as metabolism and immunity, and are closely related to the occurrence and development of tumors, cardiovascular diseases, nervous system disorders, nephropathy, and other diseases. The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases. This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of lncRNAs from the role of disease coding to acting as drug candidates, including the current status and progress in preclinical research. Cutting-edge strategies for lncRNA modulation have been summarized, including the sources of lncRNA-related drugs, such as genetic technology and small-molecule compounds, and related delivery methods. The current progress of clinical trials of lncRNA-targeting drugs is also discussed. This information will form a latest updated reference for research and development of lncRNA-based drugs.

          Graphical abstract

          This review summarizes the current knowledge on pre- and clinical transformation of lncRNAs-based drugs, covering latest strategies to target pathogenic lncRNAs, indispensable delivery systems, arising clinical trials, future directions and challenges.

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          Most cited references145

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          Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.

          To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
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            Exosomes

            Exosomes are small, single-membrane, secreted organelles of ∼30 to ∼200 nm in diameter that have the same topology as the cell and are enriched in selected proteins, lipids, nucleic acids, and glycoconjugates. Exosomes contain an array of membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosome biogenesis is a mechanism of protein quality control, and once released, exosomes have activities as diverse as remodeling the extracellular matrix and transmitting signals and molecules to other cells. This pathway of intercellular vesicle traffic plays important roles in many aspects of human health and disease, including development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases. In addition, viruses co-opt exosome biogenesis pathways both for assembling infectious particles and for establishing host permissiveness. On the basis of these and other properties, exosomes are being developed as therapeutic agents in multiple disease models.
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              Molecular mechanisms of long noncoding RNAs.

              Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. Here we discuss the emerging archetypes of molecular functions that lncRNAs execute-as signals, decoys, guides, and scaffolds. For each archetype, examples from several disparate biological contexts illustrate the commonality of the molecular mechanisms, and these mechanistic views provide useful explanations and predictions of biological outcomes. These archetypes of lncRNA function may be a useful framework to consider how lncRNAs acquire properties as biological signal transducers and hint at their possible origins in evolution. As new lncRNAs are being discovered at a rapid pace, the molecular mechanisms of lncRNAs are likely to be enriched and diversified. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Acta Pharm Sin B
                Acta Pharm Sin B
                Acta Pharmaceutica Sinica. B
                Elsevier
                2211-3835
                2211-3843
                10 October 2020
                February 2021
                10 October 2020
                : 11
                : 2
                : 340-354
                Affiliations
                [1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
                Author notes
                Article
                S2211-3835(20)30734-6
                10.1016/j.apsb.2020.10.001
                7893121
                33643816
                4d7b3734-d314-49d3-bb52-bd490be6b9a0
                © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 12 April 2020
                : 6 August 2020
                : 21 August 2020
                Categories
                Review

                lncrnas,targeted drug,gene therapy,small molecules,delivery,asncmtrna,translational medicine,clinical trials,ad, alzheimer's disease,anril, antisense noncoding rna gene at the ink4 locus,asncmtrna, antisense noncoding mitochondrial rna,aso, antisense oligonucleotide,bcar4, breast cancer anti-estrogen resistance 4,bdnf-as, brain-derived neurotrophic factor antisense,casc9, cancer susceptibility candidate 9,cdk, cyclin dependent kinase 1,chrf, cardiac hypertrophy related factor,crispr, clustered regularly interspaced short palindromic repeats,dach1, dachshund homolog 1,dancr, differentiation antagonizing non-protein coding rna,dkd, diabetic kidney disease,dpf, diphenyl furan,ebf3-as, early b cell factor 3-antisense,ene, element for nuclear expression,erbb4-ir, erb-b2 receptor tyrosine kinase 4-immunoreactivity,fda, u.s. food and drug administration,gapdh, glyceraldehyde-3-phosphate dehydrogenase,gas5, growth arrest specific 5,hisla, hif-1α-stabilizing long noncoding rna,hotair, hox transcript antisense intergenic rna,hulc, highly upregulated in liver cancer,lincrna-p21, long intergenic noncoding rna p21,lipcar, long intergenic noncoding rna predicting cardiac remodeling,lnas, locked nucleic acids,lncrnas, long non-coding rnas,malat1, metastasis associated lung adenocarcinoma transcript 1,meg3, maternally expressed gene 3,mhrt, myosin heavy chain associated rna transcripts,mm, multiple myeloma,mtlncrna, mitochondrial long noncoding rna,neat1, nuclear enriched abundant transcript 1,nkila, nf-kappab interacting lncrna,norad, non-coding rna activated by dna damage,nps, nanoparticles,oip5-as1, opa-interacting protein 5 antisense transcript 1,pd, parkinson's disease,peg, polyethylene glycol,pnas, peptide nucleic acids,phlip, ph-low insertion peptide,pto, phosphorothioate,pvt1, plasmacytoma variant translocation 1,rgd, arginine-glycine-aspartic acid peptide,risc, rna-induced silencing complex,salrna1, senescence associated long non-coding rna 1,sgrna, single guide rna,sirnas, small interfering rnas,sncmtrna, sense noncoding mitochondrial rna,snhg1, small nucleolar rna host gene 1,thril, tnf and hnrnpl related immunoregulatory,tncrna, trophoblast-derived noncoding rna,ttty15, testis-specific transcript, y-linked 15,tug1, taurine-upregulated gene 1,twist1, twist family bhlh transcription factor 1,uca1, urothelial carcinoma-associated 1,utf1, undifferentiated transcription factor 1,xist, x-inactive specific transcript
                lncrnas, targeted drug, gene therapy, small molecules, delivery, asncmtrna, translational medicine, clinical trials, ad, alzheimer's disease, anril, antisense noncoding rna gene at the ink4 locus, asncmtrna, antisense noncoding mitochondrial rna, aso, antisense oligonucleotide, bcar4, breast cancer anti-estrogen resistance 4, bdnf-as, brain-derived neurotrophic factor antisense, casc9, cancer susceptibility candidate 9, cdk, cyclin dependent kinase 1, chrf, cardiac hypertrophy related factor, crispr, clustered regularly interspaced short palindromic repeats, dach1, dachshund homolog 1, dancr, differentiation antagonizing non-protein coding rna, dkd, diabetic kidney disease, dpf, diphenyl furan, ebf3-as, early b cell factor 3-antisense, ene, element for nuclear expression, erbb4-ir, erb-b2 receptor tyrosine kinase 4-immunoreactivity, fda, u.s. food and drug administration, gapdh, glyceraldehyde-3-phosphate dehydrogenase, gas5, growth arrest specific 5, hisla, hif-1α-stabilizing long noncoding rna, hotair, hox transcript antisense intergenic rna, hulc, highly upregulated in liver cancer, lincrna-p21, long intergenic noncoding rna p21, lipcar, long intergenic noncoding rna predicting cardiac remodeling, lnas, locked nucleic acids, lncrnas, long non-coding rnas, malat1, metastasis associated lung adenocarcinoma transcript 1, meg3, maternally expressed gene 3, mhrt, myosin heavy chain associated rna transcripts, mm, multiple myeloma, mtlncrna, mitochondrial long noncoding rna, neat1, nuclear enriched abundant transcript 1, nkila, nf-kappab interacting lncrna, norad, non-coding rna activated by dna damage, nps, nanoparticles, oip5-as1, opa-interacting protein 5 antisense transcript 1, pd, parkinson's disease, peg, polyethylene glycol, pnas, peptide nucleic acids, phlip, ph-low insertion peptide, pto, phosphorothioate, pvt1, plasmacytoma variant translocation 1, rgd, arginine-glycine-aspartic acid peptide, risc, rna-induced silencing complex, salrna1, senescence associated long non-coding rna 1, sgrna, single guide rna, sirnas, small interfering rnas, sncmtrna, sense noncoding mitochondrial rna, snhg1, small nucleolar rna host gene 1, thril, tnf and hnrnpl related immunoregulatory, tncrna, trophoblast-derived noncoding rna, ttty15, testis-specific transcript, y-linked 15, tug1, taurine-upregulated gene 1, twist1, twist family bhlh transcription factor 1, uca1, urothelial carcinoma-associated 1, utf1, undifferentiated transcription factor 1, xist, x-inactive specific transcript

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