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Frontiers in Immunology 2023RNA interference (RNAi) plays pleiotropic roles in animal cells, from the post-transcriptional control of gene expression via the production of micro-RNAs, to the... (Review)
Review
RNA interference (RNAi) plays pleiotropic roles in animal cells, from the post-transcriptional control of gene expression via the production of micro-RNAs, to the inhibition of RNA virus infection. We discuss here the role of RNAi in regulating the expression of self RNAs, and particularly transposable elements (TEs), which are genomic sequences capable of influencing gene expression and disrupting genome architecture. Dicer proteins act as the entry point of the RNAi pathway by detecting and degrading RNA of TE origin, ultimately leading to TE silencing. RNAi similarly targets cellular RNAs such as repeats transcribed from centrosomes. Dicer proteins are thus nucleic acid sensors that recognize self RNA in the form of double-stranded RNA, and trigger a silencing RNA interference response.
Topics: Animals; RNA Interference; RNA, Small Interfering; DNA Transposable Elements; RNA, Double-Stranded; Mammals
PubMed: 37475864
DOI: 10.3389/fimmu.2023.1212086 -
International Journal of Molecular... Mar 2020The treatment of dominantly inherited retinal diseases requires silencing of the pathogenic allele. RNA interference to suppress gene expression suffers from wide-spread... (Review)
Review
The treatment of dominantly inherited retinal diseases requires silencing of the pathogenic allele. RNA interference to suppress gene expression suffers from wide-spread off-target effects, while CRISPR-mediated gene disruption creates permanent changes in the genome. CRISPR interference uses a catalytically inactive 'dead' Cas9 directed by a guide RNA to block transcription of chosen genes without disrupting the DNA. It is highly specific and potentially reversible, increasing its safety profile as a therapy. Pre-clinical studies have demonstrated the versatility of CRISPR interference for gene silencing both in vivo and in ex vivo modification of iPSCs for transplantation. Applying CRISPR interference techniques for the treatment of autosomal dominant inherited retinal diseases is promising but there are few in vivo studies to date. This review details how CRISPR interference might be used to treat retinal diseases and addresses potential challenges for clinical translation.
Topics: Alleles; Animals; CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Gene Expression; Gene Knockdown Techniques; Gene Silencing; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; RNA Interference; RNA, Guide, CRISPR-Cas Systems; Retinal Diseases; Transcription, Genetic
PubMed: 32230903
DOI: 10.3390/ijms21072329 -
Current Opinion in Genetics &... Oct 2021There is an impelling need to develop new therapeutics for myocardial infarction and heart failure. A novel and exciting therapeutic possibility is to achieve cardiac... (Review)
Review
There is an impelling need to develop new therapeutics for myocardial infarction and heart failure. A novel and exciting therapeutic possibility is to achieve cardiac regeneration through the stimulation of the endogenous capacity of cardiomyocytes to proliferate. Proof-of-concept evidence of microRNA-induced cardiac regeneration is available in both small and large animals using viral vectors. However, a clinically more applicable strategy is the development of lipid-mediated nanotechnologies for the administration of RNA therapeutics as synthetic molecules. The recent success of the Stable Nucleic Acid Lipid Particle (SNALP) platform for the generation of nanosized, efficient and non-inflammatory lipid nanoparticles paves the way to the development of injectable nanoformulations of microRNAs through cardiac catheterisation.
Topics: Animals; Humans; MicroRNAs; Myocardial Infarction; RNA Interference; Regeneration
PubMed: 34098251
DOI: 10.1016/j.gde.2021.05.007 -
Microbiology and Molecular Biology... Jun 2023Immune recognition of viral genome-derived double-stranded RNA (dsRNA) molecules and their subsequent processing into small interfering RNAs (siRNAs) in plants,... (Review)
Review
Immune recognition of viral genome-derived double-stranded RNA (dsRNA) molecules and their subsequent processing into small interfering RNAs (siRNAs) in plants, invertebrates, and mammals trigger specific antiviral immunity known as antiviral RNA interference (RNAi). Immune sensing of viral dsRNA is sequence-independent, and most regions of viral RNAs are targeted by virus-derived siRNAs which extensively overlap in sequence. Thus, the high mutation rates of viruses do not drive immune escape from antiviral RNAi, in contrast to other mechanisms involving specific virus recognition by host immune proteins such as antibodies and resistance (R) proteins in mammals and plants, respectively. Instead, viruses actively suppress antiviral RNAi at various key steps with a group of proteins known as viral suppressors of RNAi (VSRs). Some VSRs are so effective in virus counter-defense that potent inhibition of virus infection by antiviral RNAi is undetectable unless the cognate VSR is rendered nonexpressing or nonfunctional. Since viral proteins are often multifunctional, resistance phenotypes of antiviral RNAi are accurately defined by those infection defects of VSR-deletion mutant viruses that are efficiently rescued by host deficiency in antiviral RNAi. Here, we review and discuss infection defects of VSR-deficient RNA and DNA viruses resulting from the actions of host antiviral RNAi in model systems.
Topics: Animals; RNA Interference; Antiviral Agents; RNA, Small Interfering; RNA, Viral; DNA Viruses; RNA Viruses; Mammals
PubMed: 37052496
DOI: 10.1128/mmbr.00035-22 -
The Plant Cell Aug 2022Host-induced gene silencing (HIGS) refers to the silencing of genes in pathogens and pests by expressing homologous double-stranded RNAs (dsRNA) or artificial microRNAs... (Review)
Review
Host-induced gene silencing (HIGS) refers to the silencing of genes in pathogens and pests by expressing homologous double-stranded RNAs (dsRNA) or artificial microRNAs (amiRNAs) in the host plant. The discovery of such trans-kingdom RNA silencing has enabled the development of RNA interference-based approaches for controlling diverse crop pathogens and pests. Although HIGS is a promising strategy, the mechanisms by which these regulatory RNAs translocate from plants to pathogens, and how they induce gene silencing in pathogens, are poorly understood. This lack of understanding has led to large variability in the efficacy of various HIGS treatments. This variability is likely due to multiple factors, such as the ability of the target pathogen or pest to take up and/or process RNA from the host, the specific genes and target sequences selected in the pathogen or pest for silencing, and where, when, and how the dsRNAs or amiRNAs are produced and translocated. In this review, we summarize what is currently known about the molecular mechanisms underlying HIGS, identify key unanswered questions, and explore strategies for improving the efficacy and reproducibility of HIGS treatments in the control of crop diseases.
Topics: Gene Silencing; Plant Diseases; Plants; RNA Interference; RNA, Double-Stranded; Reproducibility of Results
PubMed: 35666177
DOI: 10.1093/plcell/koac165 -
Viruses Oct 2023Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture... (Review)
Review
Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture industry, causing major economic losses worldwide. Conventional treatment methods have proven to be ineffective in controlling these diseases. However, recent advances in RNA interference (RNAi) technology have opened new possibilities for combating shrimp viral diseases. This cutting-edge technology uses cellular machinery to silence specific viral genes, preventing viral replication and spread. Numerous studies have shown the effectiveness of RNAi-based therapies in various model organisms, paving the way for their use in shrimp health. By precisely targeting viral pathogens, RNAi has the potential to provide a sustainable and environmentally friendly solution to combat viral diseases in shrimp aquaculture. This review paper provides an overview of RNAi-based therapy and its potential as a game-changer for shrimp viral diseases. We discuss the principles of RNAi, its application in combating viral infections, and the current progress made in RNAi-based therapy for shrimp viral diseases. We also address the challenges and prospects of this innovative approach.
Topics: Animals; RNAi Therapeutics; RNA Interference; Virus Diseases; Crustacea; Aquaculture
PubMed: 37896827
DOI: 10.3390/v15102050 -
International Journal of Molecular... Mar 2021Breast cancer is very heterogenous and the most common gynaecological cancer, with various factors affecting its development. While its impact on human lives and... (Review)
Review
Breast cancer is very heterogenous and the most common gynaecological cancer, with various factors affecting its development. While its impact on human lives and national health budgets is still rising in almost all global areas, many molecular mechanisms affecting its onset and development remain unclear. Conventional treatments still prove inadequate in some aspects, and appropriate molecular therapeutic targets are required for improved outcomes. Recent scientific interest has therefore focused on the non-coding RNAs roles in tumour development and their potential as therapeutic targets. These RNAs comprise the majority of the human transcript and their broad action mechanisms range from gene silencing to chromatin remodelling. Many non-coding RNAs also have altered expression in breast cancer cell lines and tissues, and this is often connected with increased proliferation, a degraded extracellular environment, and higher endothelial to mesenchymal transition. Herein, we summarise the known abnormalities in the function and expression of long non-coding RNAs, Piwi interacting RNAs, small nucleolar RNAs and small nuclear RNAs in breast cancer, and how these abnormalities affect the development of this deadly disease. Finally, the use of RNA interference to suppress breast cancer growth is summarised.
Topics: Biomarkers, Tumor; Breast Neoplasms; Disease Management; Disease Susceptibility; Female; Gene Expression Regulation, Neoplastic; Humans; Liquid Biopsy; RNA Interference; RNA, Untranslated
PubMed: 33807045
DOI: 10.3390/ijms22063280 -
RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges.Advanced Drug Delivery Reviews Oct 2023The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi)... (Review)
Review
The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.
Topics: Humans; RNAi Therapeutics; RNA, Small Interfering; COVID-19 Vaccines; COVID-19; RNA Interference; Nanoparticles
PubMed: 37657644
DOI: 10.1016/j.addr.2023.115073 -
Pest Management Science May 2021Over 20 years ago double-stranded RNA (dsRNA) was described as the trigger of RNAi interference (RNAi)-based gene silencing. This paradigm has held since, especially... (Review)
Review
Over 20 years ago double-stranded RNA (dsRNA) was described as the trigger of RNAi interference (RNAi)-based gene silencing. This paradigm has held since, especially for insect biopesticide technologies where dsRNAs, similar to those described in 1998, are used to inhibit gene expression. In the intervening years, investigation of RNAi pathways has revealed the small RNA effectors of RNAi are diverse and rapidly evolving. The rich biology of insect small RNAs suggests potential to use multiple RNAi modes for manipulating gene expression. By exploiting different RNAi pathways, the menu of options for pest control can be expanded and could lead to better tailored solutions. Fortunately, basic delivery strategies used for dsRNA such as direct application or transgenic expression will translate well between RNAs transiting different RNAi pathways. Importantly, further engineering of RNAi-based biopesticides may provide an opportunity to address dsRNA insensitivity seen in some pests. Characterization of RNAi pathways unique to target species will be indispensable to this end and may require thinking beyond long dsRNA. © 2020 Society of Chemical Industry.
Topics: Animals; Insecta; Insecticides; Pest Control; RNA Interference; RNA, Double-Stranded
PubMed: 33078549
DOI: 10.1002/ps.6147 -
ELife Aug 2023Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target...
Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target effects. We describe artificial RNA interference (ARTi) based on synthetic, ultra-potent, off-target-free shRNAs that enable efficient and inducible suppression of any gene upon introduction of a synthetic target sequence into non-coding transcript regions. ARTi establishes a scalable loss-of-function tool with full control over on- and off-target effects.
Topics: RNA Interference; RNA, Small Interfering
PubMed: 37552050
DOI: 10.7554/eLife.84792