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Molecular Therapy. Nucleic Acids Sep 2023The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules... (Review)
Review
The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and Embase were searched from January 1, 1998, to December 30, 2022 for clinical trials using RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in the inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either -acetylgalactosamine delivery and subcutaneous administration or lipid nanoparticle delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the past decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasizes that even more RNAi-based medicines also targeting extra-hepatic tissues are likely to be available in the years to come.
PubMed: 37583575
DOI: 10.1016/j.omtn.2023.07.018 -
Cells Mar 2023Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall... (Review)
Review
INTRODUCTION
Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of studies investigating the efficacy and safety profile of GSTs in HCAs.
METHODS
A structured PubMed search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article.
RESULTS
The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed.
CONCLUSION
The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype . Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.
Topics: Animals; Cerebellar Ataxia; Trinucleotide Repeats; Spinocerebellar Degenerations; Proteins
PubMed: 37048110
DOI: 10.3390/cells12071037 -
Frontiers in Immunology 2022Glioblastoma (GBM) is the most common malignant brain tumor in adults, and immunotherapies and genetic therapies for GBM have evolved dramatically over the past decade,... (Review)
Review
Glioblastoma (GBM) is the most common malignant brain tumor in adults, and immunotherapies and genetic therapies for GBM have evolved dramatically over the past decade, but GBM therapy is still facing a dilemma due to the high recurrence rate. The inflammatory microenvironment is a general signature of tumors that accelerates epigenetic changes in GBM and helps tumors avoid immunological surveillance. GBM tumor cells and glioma-associated microglia/macrophages are the primary contributors to the inflammatory condition, meanwhile the modification of epigenetic events including DNA methylation, non-coding RNAs, and histone methylation and deacetylases involved in this pathological process of GBM, finally result in exacerbating the proliferation, invasion, and migration of GBM. On the other hand, histone deacetylase inhibitors, DNA methyltransferases inhibitors, and RNA interference could reverse the inflammatory landscapes and inhibit GBM growth and invasion. Here, we systematically review the inflammatory-associated epigenetic changes and regulations in the microenvironment of GBM, aiming to provide a comprehensive epigenetic profile underlying the recognition of inflammation in GBM.
Topics: Brain Neoplasms; Epigenesis, Genetic; Glioblastoma; Humans; Inflammation; Tumor Microenvironment
PubMed: 35572545
DOI: 10.3389/fimmu.2022.869307 -
Disease Markers 2014Many studies have shown that microRNAs (miRNAs) could play a potential role as prognostic biomarkers of tumors. The aim of this study is to summarize the global... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Many studies have shown that microRNAs (miRNAs) could play a potential role as prognostic biomarkers of tumors. The aim of this study is to summarize the global predicting role of microRNA-210 (miR-210) for survival in patients with a variety of carcinomas.
METHODS
Relevant literature was identified using PubMed and the information in eligible studies has been extracted. Then meta-analysis of hazard ratio (HR) was performed to evaluate the prognostic role of the miR-210 in different tumors.
RESULTS
This meta-analysis included 9 published studies dealing with various carcinomas. For recurrence free survival or disease free survival (RFS/DFS), the combined hazard ratio (HR) and 95% confidence interval (95% CI) of higher miR-210 expression were 2.47 [1.36, 4.46], which could significantly predict poor survival in general carcinomas. MicroRNA-210 was also a significant predictor for overall survival (OS), metastasis free survival or distant relapse free survival (MFS/DRFS), and disease specific survival (DSS). Importantly, subgroup analysis suggested that higher expression of miR-210 correlated with worse RFS/DFS, OS, and MFS/DRFS, especially in breast cancer, which were 3.36 [2.30, 4.93], 3.29 [1.65, 6.58], and 2.85 [1.76, 4.62] separately.
CONCLUSION
Our studies suggested that microRNA-210 could predict the outcome of patients with varieties of tumors, especially in breast cancers.
Topics: Biomarkers, Tumor; Carcinoma; Disease-Free Survival; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; RNA Interference
PubMed: 24591754
DOI: 10.1155/2014/106197 -
European Urology Aug 2016Short noncoding RNAs known as microRNAs (miRNAs) control protein expression through the degradation of RNA or the inhibition of protein translation. The miRNAs influence... (Review)
Review
CONTEXT
Short noncoding RNAs known as microRNAs (miRNAs) control protein expression through the degradation of RNA or the inhibition of protein translation. The miRNAs influence a wide range of biologic processes and are often deregulated in cancer. This family of small RNAs constitutes potentially valuable markers for the diagnosis, prognosis, and therapeutic choices in prostate cancer (PCa) patients, as well as potential drugs (miRNA mimics) or drug targets (anti-miRNAs) in PCa management.
OBJECTIVE
To review the currently available data on miRNAs as biomarkers in PCa and as possible tools for early detection and prognosis.
EVIDENCE ACQUISITION
A systematic review was performed searching the PubMed database for articles in English using a combination of the following terms: microRNA, miRNA, cancer, prostate cancer, miRNA profiling, diagnosis, prognosis, therapy response, and predictive marker.
EVIDENCE SYNTHESIS
We summarize the existing literature regarding the profiling of miRNA in PCa detection, prognosis, and response to therapy. The articles were reviewed with the main goal of finding a common recommendation that could be translated from bench to bedside in future clinical practice.
CONCLUSIONS
The miRNAs are important regulators of biologic processes in PCa progression. A common expression profile characterizing each tumor subtype and stage has still not been identified for PCa, probably due to molecular heterogeneity as well as differences in study design and patient selection. Large-scale studies that should provide additional important information are still missing. Further studies, based on common clinical parameters and guidelines, are necessary to validate the translational potential of miRNAs in PCa clinical management. Such common signatures are promising in the field and emerge as potential biomarkers.
PATIENT SUMMARY
The literature shows that microRNAs hold potential as novel biomarkers that could aid prostate cancer management, but additional studies with larger patient cohorts and common guidelines are necessary before clinical implementation.
Topics: Biomarkers, Tumor; Disease Management; Disease Progression; Gene Expression Profiling; Humans; Male; MicroRNAs; Prognosis; Prostatic Neoplasms
PubMed: 26806656
DOI: 10.1016/j.eururo.2015.12.054 -
Oncotarget Jul 2017Gastrointestinal cancers (GICs) mainly including esophageal, gastric and colorectal cancer, are the most common cause of cancer-related death and lead into high... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gastrointestinal cancers (GICs) mainly including esophageal, gastric and colorectal cancer, are the most common cause of cancer-related death and lead into high mortality worldwide. We performed this systematic review and meta-analysis to elucidate relationship between multiple microRNAs (miRs) expression and survival of GIC patients.
METHODS
We searched a wide range of database. Fixed-effects and random-effects models were used to calculate the pooled hazard ratio values of overall survival and disease free survival. In addition, funnel plots were used to qualitatively analyze the publication bias and verified by Begg's test while it seems asymmetry.
RESULTS
60 studies involving a total of 6225 patients (1271 with esophageal cancer, 3467 with gastric cancer and 1517 with colorectal cancer) were included in our meta-analysis. The pooled hazard ratio values of overall survival related to different miRs expression in esophageal, gastric, colorectal and gastrointestinal cancer were 2.10 (1.78-2.49), 2.02 (1.83-2.23), 2.54 (2.14-3.02) and 2.15 (1.99-2.31), respectively. We have identified a total of 59 miRs including 23 significantly up-regulated expression miRs (miR-214, miR-17, miR-20a, miR-200c, miR-107, miR-27a, etc.) and 36 significantly down-regulated expression miRs (miR-433, let-7g, miR-125a-5p, miR-760, miR-206, miR-26a, miR-200b, miR-185, etc.) correlated with poor prognosis in GIC patients. Moreover, 35 of them revealed mechanisms.
CONCLUSION
Overall, specific miRs are significantly associated with the prognosis of GIC patients and potentially eligible for the prediction of patients survival. It also provides a potential value for clinical decision-making development and may serve as a promising miR-based target therapy waiting for further elucidation.
Topics: Biomarkers, Tumor; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; MicroRNAs; Prognosis; Proportional Hazards Models; RNA Interference; RNA, Messenger
PubMed: 28402940
DOI: 10.18632/oncotarget.16679 -
Cells Jul 2019Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no... (Meta-Analysis)
Meta-Analysis
Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no standardised molecular markers that assist in determining HNC prognosis. The literature for this systematic review and meta-analysis were sourced from multiple bibliographic databases. This review followed PRISMA guidelines. The Hazard Ratio (HR) was selected as the effect size metric to independently assess overall survival (OS), disease-free survival (DFS), and prognosis. Subgroup analysis was performed for individual highly represented miRNA. A total of 6843 patients across 50 studies were included in the systematic review and 34 studies were included in the meta-analysis. Studies across 12 countries were assessed, with China representing 36.7% of all included studies. The analysis of the survival endpoints of OS and DFS were conducted separately, with the overall pooled effect size (HR) for each being 1.825 (95% CI 1.527-2.181; < 0.05) and 2.596 (95% CI 1.917-3.515; < 0.05), respectively. Subgroup analysis was conducted for impact of miR-21, 200b, 155, 18a, 34c-5p, 125b, 20a and 375 on OS, and miR-21 and 34a on DFS. The pooled results were found to be statistically significant for both OS and DFS. The meta-analysis indicated that miRNA alterations can account for an 82.5% decrease in OS probability and a 159.6% decrease in DFS probability. These results indicate that miRNAs have potential clinical value as prognostic biomarkers in HNC, with miR-21, 125b, 34c-5p and 18a, in particular, showing great potential as prognostic molecular markers. Further large scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.
Topics: Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; MicroRNAs; Prognosis; Publication Bias; RNA Interference
PubMed: 31349668
DOI: 10.3390/cells8080772 -
Frontiers in Genetics 2022Epigenomics has become a significant research interest at a time when rapid environmental changes are occurring. Epigenetic mechanisms mainly result from systems like...
Epigenomics has become a significant research interest at a time when rapid environmental changes are occurring. Epigenetic mechanisms mainly result from systems like DNA methylation, histone modification, and RNA interference. Epigenetic mechanisms are gaining importance in classical genetics, developmental biology, molecular biology, cancer biology, epidemiology, and evolution. Epigenetic mechanisms play important role in the action and interaction of plant genes during development, and also have an impact on classical plant breeding programs, inclusive of novel variation, single plant heritability, hybrid vigor, plant-environment interactions, stress tolerance, and performance stability. The epigenetics and epigenomics may be significant for crop adaptability and pliability to ambient alterations, directing to the creation of stout climate-resilient elegant crop cultivars. In this review, we have summarized recent progress made in understanding the epigenetic mechanisms in plant responses to biotic and abiotic stresses and have also tried to provide the ways for the efficient utilization of epigenomic mechanisms in developing climate-resilient crop cultivars, especially in chickpea, and other legume crops.
PubMed: 35937986
DOI: 10.3389/fgene.2022.900253 -
Genetics and Molecular Research : GMR Oct 2013Over the past several years, several microRNA (miRNA) expression profiling studies have been carried out on bronchopulmonary dysplasia (BPD) in mammalian lung tissues.... (Meta-Analysis)
Meta-Analysis Review
Over the past several years, several microRNA (miRNA) expression profiling studies have been carried out on bronchopulmonary dysplasia (BPD) in mammalian lung tissues. The most effective way to identify these important miRNAs is to systematically search for similar signatures identified in multiple independent studies. Accordingly, a meta-analysis was conducted to review published miRNA expression profiling studies that compared miRNA expression profiles between BPD lung tissues and normal lung tissues. A vote-counting strategy that considered the total number of studies and time points reporting differential expression was applied. Furthermore, cut-off criteria of statistically significant differentially expressed miRNAs as defined by the author and their predicted target genes, if available, as well as the list of up- and down-regulated miRNA features, were collected and recorded. Results of the meta-analysis revealed that four up-regulated miRNAs (miRNA-21, miRNA-34a, miRNA-431, and Let-7f) and one down-regulated miRNA (miRNA-335) were differentially expressed in BPD lung tissues compared with normal groups. In addition, eight miRNAs (miRNA-146b, miRNA-29a, miRNA-503, miRNA-411, miRNA-214, miRNA-130b, miRNA-382, and miRNA-181a-1*) were found to show differential expression not only in the process of normal lung development, but also during the progress of BPD. Finally, several meaningful target genes (such as the HPGD and NTRK genes) of common miRNAs (such as miRNA-21 and miRNA-141) were systematically predicted. These specific miRNAs may provide clues of the potential mechanisms involved in BPD. Further mechanistic and external validation studies are needed to confirm the clinical significance of these miRNAs in the development of BPD.
Topics: Bronchopulmonary Dysplasia; Case-Control Studies; Gene Expression Profiling; Gene Expression Regulation; Humans; Lung; MicroRNAs; RNA Interference; Signal Transduction
PubMed: 24301780
DOI: 10.4238/2013.October.30.4 -
Frontiers in Genetics 2022Cytokinins constitutes a vital group of plant hormones regulating several developmental processes, including growth and cell division, and have a strong influence on...
Cytokinins constitutes a vital group of plant hormones regulating several developmental processes, including growth and cell division, and have a strong influence on grain yield. Chemically, they are the derivatives of adenine and are the most complex and diverse group of hormones affecting plant physiology. In this review, we have provided a molecular understanding of the role of cytokinins in developing seeds, with special emphasis on pulses and oilseed crops. The importance of cytokinin-responsive genes including cytokinin oxidases and dehydrogenases (), isopentenyl transferase (), and cytokinin-mediated genetic regulation of seed size are described in detail. In addition, cytokinin expression in germinating seeds, its biosynthesis, source-sink dynamics, cytokinin signaling, and spatial expression of cytokinin family genes in oilseeds and pulses have been discussed in context to its impact on increasing economy yields. Recently, it has been shown that manipulation of the cytokinin-responsive genes by mutation, RNA interference, or genome editing has a significant effect on seed number and/or weight in several crops. Nevertheless, the usage of cytokinins in improving crop quality and yield remains significantly underutilized. This is primarily due to the multigene control of cytokinin expression. The information summarized in this review will help the researchers in innovating newer and more efficient ways of manipulating cytokinin expression including genes with the aim to improve crop production, specifically of pulses and oilseed crops.
PubMed: 36313429
DOI: 10.3389/fgene.2022.940660