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Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Alzheimer's & Dementia : the Journal of... Nov 2019Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive.
METHODS
A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.
RESULTS
Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.
DISCUSSION
Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.
Topics: Alzheimer Disease; Biomarkers; Brain; Case-Control Studies; Epigenomics; Humans; MicroRNAs
PubMed: 31495604
DOI: 10.1016/j.jalz.2019.06.4952 -
Molecular Neurobiology Sep 2019Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the...
Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the accumulation of amyloid-beta plaques and hyperphosphorylated tau in the brain causing a progressive decline in cognitive impairment. Small non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. A systematic review was conducted to extract all miRNA found to be significantly deregulated in the peripheral blood. These deregulated miRNAs were cross-referenced against the miRNAs deregulated in the brain at Braak Stage III. This resulted in a panel of 10 miRNAs (hsa-mir-107, hsa-mir-26b, hsa-mir-30e, hsa-mir-34a, hsa-mir-485, hsa-mir200c, hsa-mir-210, hsa-mir-146a, hsa-mir-34c, and hsa-mir-125b) hypothesised to be deregulated early in Alzheimer's disease, nearly 20 years before the onset of clinical symptoms. After network analysis of the 10 miRNAs, they were found to be associated with the immune system, cell cycle, gene expression, cellular response to stress, neuron growth factor signalling, wnt signalling, cellular senescence, and Rho GTPases.
Topics: Alzheimer Disease; Animals; Biomarkers; Brain; Gene Regulatory Networks; Humans; MicroRNAs
PubMed: 30734227
DOI: 10.1007/s12035-019-1500-y -
Ageing Research Reviews Nov 2022Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just... (Review)
Review
Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just beginning to be studied in the context of ageing and stress resistance. RNA modifications modulate gene expression by affecting translation initiation and speed, miRNA binding, RNA stability, and RNA degradation. Nonetheless, the precise underlying molecular mechanisms and physiological consequences of most alterations of the epitranscriptome are still only poorly understood. We here systematically review different types of modifications of rRNA, tRNA and mRNA, the methodology to analyze them, current challenges in the field, and human disease associations. Furthermore, we compiled evidence for a connection between individual enzymes, which install RNA modifications, and lifespan in yeast, worm and fly. We also included resistance to different stressors and competitive fitness as search criteria for genes potentially relevant to ageing. Promising candidates identified by this approach include RCM1/NSUN5, RRP8, and F33A8.4/ZCCHC4 that introduce base methylations in rRNA, the methyltransferases DNMT2 and TRM9/ALKBH8, as well as factors involved in the thiolation or A to I editing in tRNA, and finally the mA machinery for mRNA.
Topics: Aging; AlkB Homolog 8, tRNA Methyltransferase; Animals; Humans; Methyltransferases; MicroRNAs; RNA, Messenger; RNA, Ribosomal; RNA, Transfer; Saccharomyces cerevisiae
PubMed: 35908668
DOI: 10.1016/j.arr.2022.101700 -
EBioMedicine Jul 2023Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently...
BACKGROUND
Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently validated, and some results are contradictory. We provided a comprehensive evaluation of various types of cfRNA biomarkers and a full mining of the biomarker potential of new features of cfRNA.
METHODS
We first systematically reviewed reported cfRNA biomarkers and calculated dysregulated post-transcriptional events and cfRNA fragments. In 3 independent multicentre cohorts, we further selected 6 cfRNAs using RT-qPCR, built a panel called HCCMDP with AFP using machine learning, and internally and externally validated HCCMDP's performance.
FINDINGS
We identified 23 cfRNA biomarker candidates from a systematic review and analysis of 5 cfRNA-seq datasets. Notably, we defined the cfRNA domain to describe cfRNA fragments systematically. In the verification cohort (n = 183), cfRNA fragments were more likely to be verified, while circRNA and chimeric RNA candidates were neither abundant nor stable as qPCR-based biomarkers. In the algorithm development cohort (n = 287), we build and test the panel HCCMDP with 6 cfRNA markers and AFP. In the independent validation cohort (n = 171), HCCMDP can distinguish HCC patients from control groups (all: AUC = 0.925; CHB: AUC = 0.909; LC: AUC = 0.916), and performs well in distinguishing early-stage HCC patients (all: AUC = 0.936; CHB: AUC = 0.917; LC: AUC = 0.928).
INTERPRETATION
This study comprehensively evaluated full-spectrum cfRNA biomarker types for HCC detection, highlighted the cfRNA fragment as a promising biomarker type in HCC detection, and provided a panel HCCMDP.
FUNDING
National Natural Science Foundation of China, and The National Key Basic Research Program (973 program).
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; Cell-Free Nucleic Acids; Biomarkers, Tumor; ROC Curve; MicroRNAs
PubMed: 37315449
DOI: 10.1016/j.ebiom.2023.104645 -
International Journal of Molecular... Oct 2022Initially, natural antisense transcripts (NATs, natRNAs, or asRNAs) were considered repressors; however, their functions in gene regulation are diverse. Positive,... (Review)
Review
Initially, natural antisense transcripts (NATs, natRNAs, or asRNAs) were considered repressors; however, their functions in gene regulation are diverse. Positive, negative, or neutral correlations to the cognate gene expression have been noted. Although the first studies were published about 50 years ago, there is still much to be investigated regarding antisense transcripts in plants. A systematic review of scientific publications available in the Web of Science databases was conducted to contextualize how the studying of antisense transcripts has been addressed. Studies were classified considering three categories: "Natural antisense" (208), artificial antisense used in "Genetic Engineering" (797), or "Natural antisense and Genetic Engineering"-related publications (96). A similar string was used for a systematic search in the NCBI Gene database. Of the 1132 antisense sequences found for plants, only 0.8% were cited in PubMed and had antisense information confirmed. This value was the lowest when compared to fungi (2.9%), bacteria (2.3%), and mice (54.1%). Finally, we present an update for the cis-NATs identified in spp. Of the 1413 antisense transcripts found in different experiments, 25 showed concordant expressions, 22 were discordant, 1264 did not correlate with the cognate genes, and 102 presented variable results depending on the experiment.
Topics: RNA, Antisense; RNA, Plant; Saccharum; Transcription Factors; Transcription, Genetic
PubMed: 36232906
DOI: 10.3390/ijms231911603 -
International Journal of Molecular... Mar 2023Despite laparoscopy being a standardized option to diagnose pelvic endometriotic implants, non-invasive biomarkers are necessary to avoid the discomfort of invasive... (Review)
Review
Despite laparoscopy being a standardized option to diagnose pelvic endometriotic implants, non-invasive biomarkers are necessary to avoid the discomfort of invasive procedures. Recent evidence suggests a potential role of microRNAs (miRNAs) as feasible biomarkers for the early diagnosis of endometriosis. Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched PubMed, EMBASE, Scopus, Cochrane Library, and Science Direct in January 2023. We provided no restriction on the country and year of publication, and considered English published articles. We selected studies including patients with endometriosis and describing miRNA regulation in the context of endometriosis. Overall, 45 studies fulfilled the inclusion criteria, and 2045 patients with endometriosis and 1587 controls were screened. Patients were analyzed concerning miRNAs expression and sources, stage of disease, and symptoms, and compared to controls. Among DEMs, the ones with the widest delta between endometriosis patients and controls-Relative Expression ≥ 4 Log2(ratio)-were miR-145, miR-191, miR-195, miR-21-5p, miR-106b-5p, miR-195-5p, miR-451a, miR-200c, miR-20a-5p, and miR-15a-5p. Although the epigenetic regulation is partially unclear, miRNAs are valid biomarkers to diagnose endometriotic lesions in symptomatic and non-symptomatic women. MiRNAs modulation should be clarified, especially during therapies or relapse, to plan targeted management protocols.
Topics: Humans; Female; Endometriosis; Epigenesis, Genetic; MicroRNAs; Biomarkers; Liquid Biopsy
PubMed: 37047088
DOI: 10.3390/ijms24076116 -
Wiley Interdisciplinary Reviews. RNA May 2021Addiction is a chronic and relapsing brain disorder characterized by compulsive seeking despite adverse consequences. There are both heritable and epigenetic mechanisms... (Review)
Review
Addiction is a chronic and relapsing brain disorder characterized by compulsive seeking despite adverse consequences. There are both heritable and epigenetic mechanisms underlying drug addiction. Emerging evidence suggests that non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs, and circular RNAs regulate synaptic plasticity and related behaviors caused by substances of abuse. These ncRNAs modify gene expression and may contribute to the behavioral phenotypes of addiction. Among the ncRNAs, the most widely researched and impactful are miRNAs. The goal in this systematic review is to provide a detailed account of recent research involving the role of miRNAs in addiction. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA in Disease and Development > RNA in Disease.
Topics: Behavior, Addictive; Gene Expression; Humans; MicroRNAs; RNA, Circular; RNA, Long Noncoding; RNA, Untranslated
PubMed: 33336550
DOI: 10.1002/wrna.1637 -
Non-coding RNA Research Dec 2023At present, RNA-based therapy which includes therapies using non-coding RNAs (ncRNAs), antisense oligonucleotides (ASOs), and aptamers are gaining widespread attention... (Review)
Review
At present, RNA-based therapy which includes therapies using non-coding RNAs (ncRNAs), antisense oligonucleotides (ASOs), and aptamers are gaining widespread attention as possible ways to target genes in various cardiovascular diseases (CVDs), thereby serving as a promising therapeutic approach for CVDs and risk factors management. However, data are primarily in an early stage. A systematic review was carried out using literature from several databases (Pubmed, Cochrane, Scopus, and DOAJR) following the PRISMA guidelines. Of the 64 articles reviewed, 39 papers were included in this review with three main types of RNAs: aptamers, antisense oligonucleotides (ASOs), and small-interfering RNA (siRNA). All studies were human clinical trials. RNA-based therapies were demonstrated to be efficacious in treating various CVDs and controlling cardiovascular risk factors. They are generally safe and well-tolerated. However, data are still in the early stage and warrant further investigation.
PubMed: 37483458
DOI: 10.1016/j.ncrna.2023.06.002 -
CNS Neuroscience & Therapeutics Aug 2023Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological activities, among which circular RNAs (circRNAs) have been proven to be more tissue-specific and conservative. Many recent studies found the potential of circRNAs as biomarkers for many diseases, including cardiovascular diseases, cancers, and ischemic stroke. This systemic review and meta-analysis aimed to identify circRNAs as potential biomarkers for AIS.
METHODS
This study has been prospectively registered in PROSPERO (Registration No. 11 CRD42021288033). Published literature comparing circRNA expression profiles between AIS and non-AIS in human and animal models were retrieved from the articles published by January 2023 in major databases. We descriptively summarized the included studies, conducted meta-analysis under a random effects model, and did bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.
RESULTS
Totally 23 studies were included, reporting 18 distinctive upregulated and 20 distinctive downregulated circRNAs. Diagnostic meta-analysis indicated discriminative ability of the circRNAs. Furthermore, circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1 were reported with the same regulation trend in more than one study (animal studies included). GO and KEGG enrichment analyses indicated that the target genes of these five circRNAs were enriched in regulating cell proliferation, apoptosis, and oxidative stress.
CONCLUSIONS
This study demonstrates that circRNAs (circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1) generally are promising as potential biomarkers for AIS. However, due to the limited number of studies, diagnostic value of individual circRNA could not be validated. More in vitro and in vivo functional studies are needed.
Topics: Animals; Humans; RNA, Circular; Ischemic Stroke; Stroke; Biomarkers; MicroRNAs; RNA; Gene Expression Profiling; Protein Serine-Threonine Kinases
PubMed: 37186176
DOI: 10.1111/cns.14220