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

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.

Keywords: AD, Alzheimer's disease; ANRIL, antisense noncoding RNA gene at the INK4 locus; ASO, antisense oligonucleotide; ASncmtRNA; ASncmtRNA, antisense noncoding mitochondrial RNA; 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; Clinical trials; DACH1, dachshund homolog 1; DANCR, differentiation antagonizing non-protein coding RNA; DKD, diabetic kidney disease; DPF, diphenyl furan; Delivery; 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; Gene therapy; HISLA, HIF-1α-stabilizing long noncoding RNA; HOTAIR, HOX transcript antisense intergenic RNA; HULC, highly upregulated in liver cancer; LIPCAR, long intergenic noncoding RNA predicting cardiac remodeling; LNAs, locked nucleic acids; LncRNAs; MALAT1, metastasis associated lung adenocarcinoma transcript 1; MEG3, maternally expressed gene 3; MHRT, myosin heavy chain associated RNA transcripts; MM, multiple myeloma; NEAT1, nuclear enriched abundant transcript 1; NKILA, NF-kappaB interacting lncRNA; NPs, nanoparticles; Norad, non-coding RNA activated by DNA damage; OIP5-AS1, opa-interacting protein 5 antisense transcript 1; PD, Parkinson's disease; PEG, polyethylene glycol; PNAs, peptide nucleic acids; 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; SNHG1, small nucleolar RNA host gene 1; Small molecules; SncmtRNA, sense noncoding mitochondrial RNA; THRIL, TNF and HNRNPL related immunoregulatory; TTTY15, testis-specific transcript, Y-linked 15; TUG1, taurine-upregulated gene 1; TWIST1, twist family BHLH transcription factor 1; Targeted drug; TncRNA, trophoblast-derived noncoding RNA; Translational medicine; UCA1, urothelial carcinoma-associated 1; UTF1, undifferentiated transcription factor 1; XIST, X-inactive specific transcript; lincRNA-p21, long intergenic noncoding RNA p21; lncRNAs, long non-coding RNAs; mtlncRNA, mitochondrial long noncoding RNA; pHLIP, pH-low insertion peptide; sgRNA, single guide RNA; siRNAs, small interfering RNAs.

Graphical abstract

Figure 1

Representative well-studied lncRNAs involved in the different diseases mentioned in this review. LncRNAs participate in multi-faceted process in tumorigenesis and tumor metastasis such as tumor angiogenesis and EMT, involving tumor immunology and metabolism. In addition, lncRNAs have been reported to be associated with many other diseases, especially chronic diseases, including but not limited to neurological disorders, cardiovascular diseases, diabetes, and DKD, which provides a basis for drug research and development targeting lncRNAs. LncRNAs, long non-coding RNAs; EMT, epithelial mesenchymal transition; DKD, diabetic kidney disease; H19, imprinted maternally expressed transcript; PVT1, plasmacytoma variant translocation 1; NEAT1, nuclear enriched abundant transcript 1; NKILA, NF-kappaB interacting lncRNA; HISLA, HIF-1α-stabilizing long noncoding RNA; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; HOTAIR, HOX antisense intergenic RNA; UCA1, urothelial carcinoma-associated 1; XIST, X-inactive specific transcript; HULC, human universal load carrier; BCAR4, breast cancer anti-estrogen resistance 4; TncRNA, trophoblast-derived noncoding RNA; LincRNA-p21, long intergenic noncoding RNA p21; SNHG1, small nucleolar RNA host gene 1; BDNF-AS, brain-derived neurotrophic factor antisense RNA; EBF3-AS, early B cell factor 3 antisense RNA; LncDACH1, dachshund homolog 1; MHRT, myosin heavy chain associated RNA transcripts; CHRF, cardiac hypertrophy related factor; TUG1, taurine upregulated gene 1; MEG3, maternally expressed 3; THRIL, TNF and HNRNPL related immunoregulatory; SALRNA1, senescence associated long non-coding RNA 1; ANRIL, antisense non-coding RNA in the INK4 locus; Erbb4-IR, Erb-B2 receptor tyrosine kinase 4-immunoreactivity.

Figure 2

Respective optimal applications of siRNA, CRISPR/Cas9, and ASOs based on lncRNA intracellular localization. siRNAs are appropriate for cytoplasmic lncRNAs, ASOs for nuclear lncRNAs, and CRISPR/Cas9 for dual-localized lncRNAs or those with unknown cellular localization. CRISPR, clustered regularly interspaced short palindromic repeats; Cas9, CRISPR associated protein 9; sgRNA, single guide RNA; ASO, antisense oligonucleotide; RISC, RNA-induced silencing complex.

Figure 3

Mainstream surface modifications for liposomes/lipid nanoparticles, as well as liposome–exosome hybrids in lncRNA drug delivery. Liposomes/lipid nanoparticles can be moderated by ligands, PEG, RGD, aptamers, linkers, or antibodies to improve delivery performance. In addition, liposome–exosome hybrids are new drug delivery agents that can be successfully applied in preclinical experiments. PEG, polyethylene glycol; RGD, arginine-glycine-aspartic acid peptide.

Figure 4

Schematic illustration of peptide-decorated exosomes for targeted lncRNA delivery. Exosome producers can be living cells, in particular, cells from patients themselves. The exosome membrane is always modified with specific peptides binding to their receptors within the target tissue, thus enhancing the specificity of exosome delivery.

Figure 5

Schematic illustration of the mechanism of Andes-1537. The binding between Andes-1537 and ASncmtRNA activates RNase H degradation in this binding region. DICER then releases mitochondrial miRNAs, mainly hsa-miR-4485, inducing an increase in some specific nuclear-encoded miRNAs. These miRNAs (such as hsa-miR-5096 and hsa-miR-3609) downregulate cell cycle progression factors including cyclin B1, cyclin D1, CDK1, CDK4, and survivin, and consequently reduce cell cycle and tumor cells. Further details can be found in the previous study [Adapted with modification from Ref. © The Author(s) 2019]. ASncmtRNA, antisense non-coding mitochondrial RNA; CDK, cyclin dependent kinase.