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International Journal of Cancer Jan 2020
Topics: Humans; Publishing; RNA Interference; RNA, Small Interfering
PubMed: 31454067
DOI: 10.1002/ijc.32641 -
Nature Communications Aug 2023Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster,...
Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2's functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.
Topics: Animals; DNA Helicases; Drosophila melanogaster; Drosophila Proteins; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNA-Binding Proteins
PubMed: 37633971
DOI: 10.1038/s41467-023-40919-1 -
Wiley Interdisciplinary Reviews. RNA 2024RNA-based therapeutics offer a flexible and reversible approach for treating genetic disorders, such as antisense oligonucleotides, RNA interference, aptamers, mRNA... (Review)
Review
RNA-based therapeutics offer a flexible and reversible approach for treating genetic disorders, such as antisense oligonucleotides, RNA interference, aptamers, mRNA vaccines, and RNA editing. In recent years, significant advancements have been made in RNA base editing to correct disease-relevant point mutations. These achievements have significantly influenced the fields of biotechnology, biomedical research and therapeutics development. In this article, we provide a comprehensive overview of the design and performance of contemporary RNA base editors, including A-to-I, C-to-U, A-to-mA, and U-to-Ψ. We compare recent innovative developments and highlight their applications in disease-relevant contexts. Lastly, we discuss the limitations and future prospects of utilizing RNA base editing for therapeutic purposes. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Development.
Topics: RNA; CRISPR-Cas Systems; Gene Editing; Oligonucleotides, Antisense; RNA Interference
PubMed: 38576085
DOI: 10.1002/wrna.1844 -
Wiley Interdisciplinary Reviews. RNA Jul 2021RNA interference (RNAi) technology has been used for almost two decades to study gene functions and in therapeutic approaches. It uses cellular machinery and small,... (Review)
Review
RNA interference (RNAi) technology has been used for almost two decades to study gene functions and in therapeutic approaches. It uses cellular machinery and small, designed RNAs in the form of synthetic small interfering RNAs (siRNAs) or vector-based short hairpin RNAs (shRNAs), and artificial miRNAs (amiRNAs) to inhibit a gene of interest. Artificial miRNAs, known also as miRNA mimics, shRNA-miRs, or pri-miRNA-like shRNAs have the most complex structures and undergo two-step processing in cells to form mature siRNAs, which are RNAi effectors. AmiRNAs are composed of a target-specific siRNA insert and scaffold based on a natural primary miRNA (pri-miRNA). siRNAs serve as a guide to search for complementary sequences in transcripts, whereas pri-miRNA scaffolds ensure proper processing and transport. The dynamics of siRNA maturation and siRNA levels in the cell resemble those of endogenous miRNAs; therefore amiRNAs are safer than other RNAi triggers. Delivered as viral vectors and expressed under tissue-specific polymerase II (Pol II) promoters, amiRNAs provide long-lasting silencing and expression in selected tissues. Therefore, amiRNAs are useful therapeutic tools for a broad spectrum of human diseases, including neurodegenerative diseases, cancers and viral infections. Recent reports on the role of sequence and structure in pri-miRNA processing may contribute to the improvement of the amiRNA tools. In addition, the success of a recently initiated clinical trial for Huntington's disease could pave the way for other amiRNA-based therapies, if proven effective and safe. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action RNA in Disease and Development > RNA in Disease.
Topics: Genetic Vectors; Humans; MicroRNAs; RNA Interference; RNA Processing, Post-Transcriptional; RNA, Small Interfering
PubMed: 33386705
DOI: 10.1002/wrna.1640 -
Trends in Plant Science Jan 2024Plants use RNA interference for basal antiviral immunity, but emerging evidence suggests that additional RNA-targeting defense mechanisms also defend against invading...
Plants use RNA interference for basal antiviral immunity, but emerging evidence suggests that additional RNA-targeting defense mechanisms also defend against invading viruses. Recent advancements in the understanding of RNA decay, RNA quality control, and N6-methyladenosine (mA) RNA modifications have unveiled new insights into the molecular arms race between plants and viruses.
Topics: RNA Interference; Plant Diseases; RNA; Plant Viruses; Plants
PubMed: 37953079
DOI: 10.1016/j.tplants.2023.10.014 -
ACS Biomaterials Science & Engineering Sep 2021Photodynamic therapy (PDT) is a noninvasive and effective local treatment for cancers that produces selective damage to target tissues and cells. However, PDT alone is... (Review)
Review
Photodynamic therapy (PDT) is a noninvasive and effective local treatment for cancers that produces selective damage to target tissues and cells. However, PDT alone is unlikely to completely inhibit tumor metastasis and/or local tumor recurrence. RNA interference (RNAi) is a phenomenon of gene silencing mediated by exogenous or endogenous double-stranded RNA (dsRNA). RNAi has entered a golden period of development, with the approval of four treatments employing RNAi. PDT in combination with RNAi therapy to inhibit related targets has been a research hotspot, with better clinical outcomes than monotherapy. In this review, the progress of PDT and small interfering RNA (siRNA) targeting different genes is discussed, while the achievements of the combined immunotherapy are reviewed.
Topics: Neoplasms; Photochemotherapy; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNAi Therapeutics
PubMed: 34427082
DOI: 10.1021/acsbiomaterials.1c00765 -
NEJM Evidence Dec 2023BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich...
BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)
Topics: Humans; Apolipoprotein C-III; RNA Interference; Hypertriglyceridemia
PubMed: 38320498
DOI: 10.1056/EVIDoa2200325 -
Advances in Experimental Medicine and... 2020Ribonucleic acid (RNA) is being exploited and understood in its many aspects of function and structure for development of valuable tools in the therapeutics of various... (Review)
Review
Ribonucleic acid (RNA) is being exploited and understood in its many aspects of function and structure for development of valuable tools in the therapeutics of various diseases such as cardiovascular etc. The expanded knowledge regarding function of RNA in the genomics and inside the cell has dramatically changed the therapeutic strategies in the past few years. RNA has become a spotlight of attention for developing novel therapeutic schemes and hence variety of therapeutic strategies is being coming into the picture that includes RNA interference, use of aptamers, role of microRNA (miRNA) that can alter the complex gene expression patterns. It is due to the fact that RNA offers various advantages in disease management as it can be edited and modified in its various forms such as secondary and tertiary structures. Although scientists are in process of manufacturing RNA-targeting therapies using variety of endogenous gene silencing regulators, Small interfering RNAs (Si RNAs), aptamers and microRNA for cardiovascular diseases yet the development of a novel, risk free therapeutic strategy is a major challenge and need of the hour in cardiovascular medicine. In this regard these agents are required to overcome pleothra of barriers such as stability of drug targets, immunogenicity, adequate binding, targeted delivery etc. to become effective drugs. Recent years have witnessed the progress of RNA therapeutic strategies in cardiovascular diseases that are likely to significantly expand the cardiovascular therapeutic repertoire within the next decade. The present manuscript has been compiled to summarize various approaches of siRNA based therapies in cardiovascular diseases along with the advantages, outcomes and limitations if any in this regard. In addition, the future prospects of RNA therapeutic modalities in cardiovascular diseases are summarized.
Topics: Aptamers, Nucleotide; Cardiovascular Diseases; Gene Silencing; Humans; MicroRNAs; RNA Interference; RNA, Small Interfering; RNAi Therapeutics
PubMed: 32285425
DOI: 10.1007/978-981-15-1671-9_23 -
Theranostics 2021The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an... (Review)
Review
The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.
Topics: Animals; Biomimetic Materials; Biomimetics; Gene Expression Regulation; Gene Silencing; Humans; MicroRNAs; Molecular Mimicry; RNA Interference; RNA, Small Interfering
PubMed: 34522211
DOI: 10.7150/thno.62642 -
Angewandte Chemie (International Ed. in... May 2023Mitochondrial RNA (mtRNA) plays a critical role in synthesis of mitochondrial proteins. Interfering mtRNA is a highly effective way to induce cell apoptosis. Herein, we...
Mitochondrial RNA (mtRNA) plays a critical role in synthesis of mitochondrial proteins. Interfering mtRNA is a highly effective way to induce cell apoptosis. Herein, we report a near-infrared (NIR) light-mediated mitochondrial RNA modification approach for long-term imaging and effective suppression of tumors. A tumor-targetable NIR fluorescent probe f-CRI consisting of a cyclic RGD peptide, a NIR fluorophore IR780, and a singlet oxygen ( O )-labile furan group for RNA modification was rationally designed and synthesized. This probe was demonstrated to dominantly accumulate in cellular mitochondria and could be covalently conjugated onto mtRNA upon 808 nm irradiation resulting in prolonged retention in tumors. More notably, this covalent modification of mtRNA by f-CRI could perturb the function of mitochondria leading to remarkable tumor suppression. We thus envision that our current approach would offer a potential approach for cancer RNA interference therapeutics.
Topics: Humans; RNA, Mitochondrial; RNA Interference; Neoplasms; Photochemotherapy; Mitochondria; Fluorescent Dyes
PubMed: 36912594
DOI: 10.1002/anie.202218969