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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 -
International Journal of Cancer Dec 2022To inform optimal approaches for detecting anal precancers, we performed a systematic review and meta-analysis of the diagnostic accuracy of anal cancer screening tests... (Meta-Analysis)
Meta-Analysis
To inform optimal approaches for detecting anal precancers, we performed a systematic review and meta-analysis of the diagnostic accuracy of anal cancer screening tests in different populations with elevated risk for anal cancer. We conducted a literature search of studies evaluating tests for anal precancer and cancer (anal intraepithelial neoplasia grade 2 or worse, AIN2+) published between January 1, 1997 to September 30, 2021 in PubMed and Embase. Titles and abstracts were screened for inclusion and included articles underwent full-text review, data abstraction and quality assessment. We estimated the prevalence of AIN2+ and calculated summary estimates and 95% confidence intervals (CI) of test positivity, sensitivity and specificity and predictive values of various testing strategies, overall and among population subgroups. A total of 39 articles were included. The prevalence of AIN2+ was 20% (95% CI, 17-29%), and ranged from 22% in men who have sex with men (MSM) living with HIV to 13% in women and 12% in MSM without HIV. The sensitivity and specificity of cytology and HPV testing were 81% and 62% and 92% and 42%, respectively, and 93% and 33%, respectively for cytology and HPV co-testing. AIN2+ risks were similar among those testing positive for cytology, HPV, or co-testing. Limited data on other biomarkers (HPV E6/E7 mRNA and p16/Ki-67 dual stain), suggested higher specificity, but lower sensitivity compared with anal cytology and HPV. Our findings provide important evidence for the development of clinical guidelines using anal cytology and HPV testing for anal cancer screening.
Topics: Anus Neoplasms; Early Detection of Cancer; Female; HIV Infections; Homosexuality, Male; Humans; Ki-67 Antigen; Male; Papillomaviridae; Papillomavirus Infections; RNA, Messenger; Sexual and Gender Minorities
PubMed: 35793241
DOI: 10.1002/ijc.34199 -
Frontiers in Immunology 2021There is a significant research gap in meta-analysis on the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines. This study analyzed the efficacy of... (Meta-Analysis)
Meta-Analysis
There is a significant research gap in meta-analysis on the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines. This study analyzed the efficacy of COVID-19 vaccines. Published phase I, phase II, and phase III trials analyzing safety and immunogenicity and phase III randomized clinical trials evaluating the efficacy of COVID-19 vaccines were included. We searched MEDLINE, Scopus, and The Lancet for published articles evaluating the relative reduction in COVID-19 risk after vaccination. Selected literatures were published between December 15, 2019 and May 15, 2021 on the safety, efficacy, and immunogenicity of COVID-19 vaccines. This meta-analysis included studies that confirmed cases of COVID-19 using reverse transcriptase polymerase chain reaction. This study detected 8,926 eligible research articles published on COVID-19 vaccines. Of these, 25 studies fulfilled the inclusion criteria. Among the selected articles, 19 randomized clinical trials, 2 non-randomized clinical trials, and 3 observational studies were analyzed. Seven (28%) studies were included in the meta-analysis. The efficacy of the adenovirus vector vaccine was 73% (95% CI = 69-77) and that of the messenger RNA (mRNA) vaccine was 85% (95% CI = 82-88) in participants aged ≥18 years. There are no reports of clinical trials in participants aged under 16 years. The production of neutralizing antibodies against receptor-binding domains (RBDs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in >90% of the vaccinated samples was reported within 0-30 days of the first or the second dose of the vaccine. Pain at the injection site was the most common local symptom in people receiving mRNA vaccines (29%-85% of participants). Fever (0.2%-95%) was the most prevalent in people receiving adenovirus vector vaccines, and fatigue (8.4%-55%) was the most common side effect in people receiving the mRNA vaccines. Studies suggest that mRNA vaccines and adenovirus vector vaccines can provide moderate to high protection against COVID-19 infection in people over 18 years. Evidence of the long-term protection of the vaccines in people aged under 16 years against the multiple variants of COVID-19 are limited. This study will provide an integrated evaluation on the efficacy, safety, and immunogenicity of the COVID-19 vaccines.
Topics: Adolescent; Adult; Aged; Antibodies, Neutralizing; COVID-19; COVID-19 Vaccines; Humans; Immunogenicity, Vaccine; Injections, Intramuscular; Middle Aged; Pain; Randomized Controlled Trials as Topic; SARS-CoV-2; Young Adult
PubMed: 34707602
DOI: 10.3389/fimmu.2021.714170 -
Nature Communications May 2022Safety and effectiveness of COVID-19 vaccines during pregnancy is a particular concern affecting vaccination uptake by this vulnerable group. Here we evaluated evidence... (Meta-Analysis)
Meta-Analysis
Safety and effectiveness of COVID-19 vaccines during pregnancy is a particular concern affecting vaccination uptake by this vulnerable group. Here we evaluated evidence from 23 studies including 117,552 COVID-19 vaccinated pregnant people, almost exclusively with mRNA vaccines. We show that the effectiveness of mRNA vaccination against RT-PCR confirmed SARS-CoV-2 infection 7 days after second dose was 89·5% (95% CI 69·0-96·4%, 18,828 vaccinated pregnant people, I = 73·9%). The risk of stillbirth was significantly lower in the vaccinated cohort by 15% (pooled OR 0·85; 95% CI 0·73-0·99, 66,067 vaccinated vs. 424,624 unvaccinated, I = 93·9%). There was no evidence of a higher risk of adverse outcomes including miscarriage, earlier gestation at birth, placental abruption, pulmonary embolism, postpartum haemorrhage, maternal death, intensive care unit admission, lower birthweight Z-score, or neonatal intensive care unit admission (p > 0.05 for all). COVID-19 mRNA vaccination in pregnancy appears to be safe and is associated with a reduction in stillbirth.
Topics: COVID-19; COVID-19 Vaccines; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Placenta; Pregnancy; Premature Birth; RNA, Messenger; SARS-CoV-2; Stillbirth; Vaccination
PubMed: 35538060
DOI: 10.1038/s41467-022-30052-w -
JAMA Pediatrics Apr 2023Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform clinicians, families, and policy makers.
OBJECTIVE
To evaluate the efficacy and safety of mRNA COVID-19 vaccines in children aged 5 to 11 years in a systematic review and meta-analysis.
DATA SOURCES
PubMed and Embase databases were searched on September 29, 2022, without language restrictions.
STUDY SELECTION
Randomized clinical trials and observational studies comparing vaccinated vs unvaccinated children aged 5 to 11 years and reporting efficacy or safety outcomes were included. Studies reporting safety outcomes in vaccinated children only (ie, no control group) were also included.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently extracted relevant data from each study. Odds ratios (ORs) for efficacy and safety outcomes and incidences of adverse events (AEs) following vaccination were synthesized using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines.
MAIN OUTCOMES AND MEASURES
The primary outcome was SARS-CoV-2 infections with or without symptoms. The secondary outcomes included symptomatic SARS-CoV-2 infections, hospitalizations, and multisystem inflammatory syndrome in children. The incidences of each AE following vaccination were also evaluated.
RESULTS
Two randomized clinical trials and 15 observational studies involving 10 935 541 vaccinated children (median or mean age range, 8.0-9.5 years) and 2 635 251 unvaccinated children (median or mean age range, 7.0-9.5 years) were included. Two-dose mRNA COVID-19 vaccination compared with no vaccination was associated with lower risks of SARS-CoV-2 infections with or without symptoms (OR, 0.47; 95% CI, 0.35-0.64), symptomatic SARS-CoV-2 infections (OR, 0.53; 95% CI, 0.41-0.70), hospitalizations (OR, 0.32; 95% CI, 0.15-0.68), and multisystem inflammatory syndrome in children (OR, 0.05; 95% CI, 0.02-0.10). Two randomized clinical trials and 5 observational studies investigated AEs among vaccinated children. Most vaccinated children experienced at least 1 local AE following the first injection (32 494 of 55 959 [86.3%]) and second injection (28 135 of 46 447 [86.3%]). Vaccination was associated with a higher risk of any AEs compared with placebo (OR, 1.92; 95% CI, 1.26-2.91). The incidence of AEs that prevented normal daily activities was 8.8% (95% CI, 5.4%-14.2%) and that of myocarditis was estimated to be 1.8 per million (95% CI, 0.000%-0.001%) following the second injection.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, COVID-19 mRNA vaccines among children aged 5 to 11 years were associated with measures of efficacy in preventing SARS-CoV-2 infection and severe COVID-19-related illnesses. While most children developed local AEs, severe AEs were rare, and most of AEs resolved within several days. These data provide evidence for future recommendations.
Topics: Humans; Child; Child, Preschool; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Parents
PubMed: 36689319
DOI: 10.1001/jamapediatrics.2022.6243 -
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 -
Trends in Genetics : TIG Feb 2017Our understanding of gene expression has come far since the 'one-gene one-polypeptide' hypothesis proposed by Beadle and Tatum. In this review, we address the gradual... (Review)
Review
Our understanding of gene expression has come far since the 'one-gene one-polypeptide' hypothesis proposed by Beadle and Tatum. In this review, we address the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an internal ribosome entry site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, here we highlight a process of noncanonical translation, IRES-mediated translation, that is a growing source for understanding complex inheritance, the elucidation of disease mechanisms, and the discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of both translational and disease mechanisms.
Topics: Animals; Genetic Diseases, Inborn; Humans; Internal Ribosome Entry Sites; Mammals; Molecular Targeted Therapy; Protein Biosynthesis; RNA, Messenger
PubMed: 28012572
DOI: 10.1016/j.tig.2016.11.007 -
BMJ Open Jun 2023To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022.
STUDY SELECTION
Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model.
RESULTS
Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82).
CONCLUSION
Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk.
Topics: Humans; Male; COVID-19; COVID-19 Vaccines; Myocarditis; Pericarditis; RNA, Messenger; SARS-CoV-2; Vaccination
PubMed: 37339840
DOI: 10.1136/bmjopen-2022-065687 -
Experimental Hematology & Oncology Feb 2021Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin's lymphomas (NHL). DLBCL is an aggressive malignancy that displays a great... (Review)
Review
Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin's lymphomas (NHL). DLBCL is an aggressive malignancy that displays a great heterogeneity in terms of morphology, genetics and biological behavior. While a sustained complete remission is obtained in the majority of patients with standard immunochemotherapy, patients with refractory of relapsed disease after first-line treatment have a poor prognosis. This patient group represents an important unmet need in lymphoma treatment. In recent years, improved understanding of the underlying molecular pathogenesis had led to new classification and prognostication tools, including the development of cell-free biomarkers in liquid biopsies. Although the majority of studies have focused on the use of cell-free fragments of DNA (cfDNA), there has been an increased interest in circulating-free coding and non-coding RNA, including messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA), as well as RNA encapsulated in extracellular vesicles or tumor-educated platelets (TEPs). We performed a systematic search in PubMed to identify articles that evaluated circulating RNA as diagnostic, subtype, treatment response or prognostic biomarkers in a human DLBCL population. A total of 35 articles met the inclusion criteria. The aim of this systematic review is to present the current understanding of circulating RNA molecules as biomarker in DLBCL and to discuss their future potential.
PubMed: 33593440
DOI: 10.1186/s40164-021-00208-3 -
European Journal of Clinical... Nov 2022Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG.
METHODS
Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022.
RESULTS
Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions.
CONCLUSIONS
In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.
Topics: Apolipoprotein B-48; Apolipoprotein C-III; Cholesterol, LDL; Humans; Hyperlipidemias; Hypertriglyceridemia; Oligonucleotides; Oligonucleotides, Antisense; RNA, Messenger; Randomized Controlled Trials as Topic; Triglycerides
PubMed: 35851450
DOI: 10.1111/eci.13841