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ABSTRACT
Introduction
lncRNAs are major players in regulatory networks orchestrating multiple cellular functions, such as 3D chromosomal interactions, epigenetic modifications, gene expression and others. Due to progress in the development of nucleic acid-based therapeutics, lncRNAs potentially represent easily accessible therapeutic targets.
Areas covered
Currently, significant efforts are directed at studies that can tap the enormous therapeutic potential of lncRNAs. This review describes recent developments in this field, particularly focusing on clinical applications.
Expert opinion
Extensive druggable target range of lncRNA combined with high specificity and accelerated development process of nucleic acid-based therapeutics open new prospects for treatment in areas of extreme unmet medical need, such as genetic diseases, aggressive cancers, protein deficiencies, and subsets of common diseases caused by known mutations. Although currently wide acceptance of lncRNA-targeting nucleic acid-based therapeutics is impeded by the need for parenteral or direct-to-CNS administration, development of less invasive techniques and orally available/BBB-penetrant nucleic acid-based therapeutics is showing early successes. Recently, mRNA-based COVID-19 vaccines have demonstrated clinical safety of all aspects of nucleic acid-based therapeutic technology, including multiple chemical modifications of nucleic acids and nanoparticle delivery. These trends position lncRNA-targeting drugs as significant players in the future of drug development, especially in the area of personalized medicine.
Article highlights
While 1% of the genome codes for proteins, more than 2/3 are actively transcribed as ncRNAs with extensive structural and regulatory functions, supporting the concept of the cell as an ‘RNA machine.’
ncRNAs provide access for therapeutic modulation of all major cellular pathways, including 3D chromosomal interactions, epigenetic modifications, transcription, splicing, mRNA and protein stability and transport, translation and degradation, apoptosis, autophagy, and other processes.
Targeting gene-specific lncRNA components of regulatory protein complexes can potentially lead to fewer detrimental off-target effects than targeting their protein components.
The ‘wet lab’ exploration of lncRNA mechanisms is now augmented by machine learning-based computational approaches that can predict the composition of ncRNA-mediated regulatory networks and lncRNA-disease associations.
Despite the tremendous potential of lncRNA-targeted therapeutics, so far none of such drugs has reached the clinic. This review focuses on the newly discovered lncRNA-mediated biological mechanisms and proposes possible ways to target them with NBTs.
Abbreviations
| AAV | = | adeno-associated virus |
| ADAR | = | adenosine deaminase, RNA-specific |
| ADORA2A | = | adenosine A2A receptor |
| AKT1 | = | AKT serine/threonine kinase 1 |
| ALKBH5 | = | AlkB homolog 5, RNA demethylase |
| ANRIL | = | antisense noncoding RNA in the INK4 locus |
| APOA1 | = | apolipoprotein A-I |
| ASO | = | antisense oligonucleotides |
| Bcl11b | = | BAF chromatin remodeling complex subunit BCL11B |
| BDNF | = | brain derived neurotrophic factor |
| c9orf72 | = | chromosome 9 open reading frame 72 |
| CAS9 | = | CRISPR-associated protein 9 |
| CCDC163P | = | coiled-coil domain containing 163 |
| CEBPA | = | CCAAT/enhancer-binding protein, alpha or C/EBPα |
| ceRNA | = | competing endogenous RNA |
| CFTR | = | cystic fibrosis transmembrane conductance regulator |
| CKMT2 | = | creatine kinase, mitochondrial 2 |
| CRISPR | = | clustered regularly interspaced short palindromic repeats |
| CTCF | = | CCCTC-binding factor |
| Ddx5 | = | DEAD‐box helicase 5 |
| DMP1 | = | dentin matrix protein-1 |
| DNM3OS | = | dynamin 3 opposite strand |
| DNMT1 | = | DNA (cytosine-5)-methyltransferase 1 |
| eEF1A1 | = | eukaryotic translation elongation factor 1 alpha 1 |
| EGF | = | epidermal growth factor |
| EGFR | = | epidermal growth factor receptor |
| EIF3G | = | eukaryotic translation initiation factor 3 subunit G |
| eRNA | = | enhancer RNA |
| EZH2 | = | enhancer of zeste 2 polycomb repressive complex 2 subunit |
| FOXM1 | = | forkhead box M1 |
| FSCN1 | = | fascin actin-bundling protein 1 |
| FXN | = | frataxin |
| GATA3 | = | GATA-binding protein 3 |
| Gdnf | = | glial cell line-derived neurotrophic factor |
| HLA | = | human leukocyte antigen |
| HNF4A | = | hepatocyte nuclear factor 4-alpha |
| HOTAIR | = | HOX transcript antisense RNA, noncoding |
| HuR | = | ELAV-like RNA-binding protein 1; ELAVL1 |
| IFNA | = | interferon-α1 or IFN-α1 |
| IGF2 | = | insulin-like growth factor 2 |
| invSINEB2 | = | inverted short interspersed nuclear element B2 |
| iPSC | = | induced pluripotent stem cell |
| IRES | = | internal ribosome entry site |
| IRF8 | = | interferon regulatory factor 8 |
| KCNQ1 | = | potassium channel, voltage-gated, KQT-like subfamily, member 1 |
| KDM4A | = | lysine demethylase 4A |
| KHPS1 | = | sphingosine kinase 1 (SPHK1) antisense transcript |
| lincRNA | = | long intergenic non-coding RNAs |
| LSD1 | = | lysine demethylase 1; KDM1A |
| LYPLAL1 | = | lysophospholipase-like 1 |
| MAGI2 | = | membrane-associated guanylate kinase, WW and PDZ domains-containing, 2 |
| MALAT1 | = | metastasis-associated lung adenocarcinoma transcript 1 |
| MAPT | = | microtubule-associated protein tau antisense 1 |
| MAT2A | = | methionine adenosyltransferase 2A |
| MEG3 | = | maternally expressed gene 3 |
| MIND | = | minimally invasive intranasal depot |
| MIR | = | mammalian-wide interspersed repeats |
| MMACHC | = | metabolism of cobalamin associated c |
| mTOR | = | mammalian target of rapamycin; mechanistic target of rapamycin |
| MYOD | = | myogenic differentiation antigen 1 |
| NAT | = | natural antisense transcripts |
| NBT | = | nucleic acid-based therapeutic |
| NEAT1 | = | noncoding nuclear-enriched abundant transcript 1 |
| NELF | = | negative elongation factor complex, member A |
| PAM | = | Pax7 associated muscle lncRNA |
| PRC2 | = | polycomb repressive complex 2 |
| PRDX1 | = | peroxiredoxin |
| PRMT | = | protein arginine methyltransferase 5 |
| pRNA | = | promoter RNA; PROMPT; promoter antisense RNA (PAS) |
| RAB11B | = | RAS-associated protein RAB11B |
| RHPN1 | = | rhophilin 1 |
| SCN1A | = | sodium voltage-gated channel, alpha subunit 1 |
| Sema3A | = | semaphorin 3A |
| seRNA | = | super enhancer RNA |
| SINEUP | = | inverted SINEB2 sequence-mediated upregulating molecules |
| siRNA | = | small interfering RNA |
| SMAD3 | = | SMAD family member 3 |
| SMAD4 | = | SMAD family member 4 |
| SMN2 | = | survival of motor neuron 2 |
| SRSF1 | = | splicing factor, serine/arginine-rich, 1 |
| STAT3 | = | signal transducer and activator of transcription 3 |
| STING | = | stimulator of interferon response cGAMP interactor 1 |
| TAF15 | = | TATA-box binding protein associated factor 15 |
| TALEN | = | transcription activator-like effector nucleases |
| TESK2 | = | testis-specific protein kinase 2 |
| TET1 | = | TET methylcytosine dioxygenase 1 |
| TGF-β | = | transforming growth factor, beta-1; TGFB1 |
| ThymoD | = | thymocyte differentiation factor |
| Timp2 | = | tissue inhibitor of metalloproteinases 2 |
| UBE3A | = | ubiquitin protein ligase E3A |
| USP14 | = | ubiquitin-specific protease 14 |
| VIRMA | = | vir-like m6A methyltransferase-associated protein or KIAA1429 |
| vlincRNA | = | very long intergenic non-coding RNA or macroRNA |
| WWOX | = | WW domain containing oxidoreductase |
| YY1 | = | Yin Yang 1 |
| ZEB2 | = | zinc finger E box-binding homeobox 2 |
| ZRANB2 | = | zinc finger RANBP2-type containing 2 |
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.