Targeting circular RNAs as a therapeutic approach: current strategies and challenges

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 21, 2021

Abstract Significant progress has been made in circular RNA (circRNA) research recent years. Increasing evidence suggests that circRNAs play important roles many cellular processes, and their dysregulation is implicated the pathogenesis of various diseases. CircRNAs are highly stable usually expressed a tissue- or cell type-specific manner. Therefore, they currently being explored as potential therapeutic targets. Gain-of-function loss-of-function approaches typically performed using circRNA expression plasmids interference-based strategies, respectively. These strategies have limitations can be mitigated nanoparticle exosome delivery systems. Furthermore, developments show cre-lox system used to knockdown cell-specific While still early stages development, CRISPR/Cas13 shown promise knocking down with high specificity efficiency. In this review, we describe properties functions highlight significance disease. We summarize overexpress approach. Lastly, discuss major challenges propose future directions for development circRNA-based therapeutics.

Language: Английский

---

A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Vaccines, Journal Year: 2019, Volume and Issue: 7(2), P. 37 - 37

Published: April 24, 2019

This review provides a comparison of the theoretical issues and experimental findings for plasmid DNA mRNA vaccine technologies. While both have been under development since 1990s, in recent years, significant excitement has turned to despite licensure several veterinary vaccines. Both required efforts increase their potency either via manipulating directly or through addition adjuvants immunomodulators as well delivery systems formulations. The greater inherent inflammatory nature vaccines is discussed its potential immunological utility toxicity. status clinical trials described along with vaccines, specifically immunogenicity licensed select candidates human trials.

Language: Английский

---

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

Pharmacological Reviews, Journal Year: 2020, Volume and Issue: 72(4), P. 862 - 898

Published: Sept. 14, 2020

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 RNAs may be used selectively act on proteins, transcripts, genes that cannot targeted by conventional or proteins. Although development faces unparalleled challenges, many strategies have been developed improve metabolic stability intracellular delivery. A number approved for medical use, aptamers (e.g., pegaptanib) mechanistically protein target interfering patisiran givosiran) antisense oligonucleotides inotersen golodirsen) directly interfere with Furthermore, guide are essential components novel gene editing modalities, mRNA therapeutics under replacement therapy vaccination, those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional motifs highly structured form binding pockets clefts accessible molecules. Many natural, semisynthetic, synthetic antibiotics aminoglycosides, tetracyclines, macrolides, oxazolidinones, phenicols) can bind ribosomal achieve inhibition bacterial infections. Therefore, there is growing interest in developing small-molecule amenable oral administration, some risdiplam branaplam) entered clinical trials. Here, we review pharmacology medications, a focus recent progresses strategies. Challenges druggable entities identification viable targets selective binders discussed.

Significance Statement

With understanding functions critical roles diseases, well RNA-related technologies, therapeutics. This comprehensive presents both focusing mechanisms action, most progress, existing challenges.

Language: Английский

---

Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(2)

Published: Feb. 24, 2020

Abstract Compelling evidence has demonstrated the potential functions of circular RNAs (circRNAs) in breast cancer (BC) tumorigenesis. Nevertheless, underlying mechanism by which circRNAs regulate BC progression is still unclear. The purpose present research was to investigate novel circRNA circRNF20 (hsa_circ_0087784) and its role BC. CircRNA microarray sequencing revealed that one upregulated transcripts samples. Increased level predicted poor clinical outcome specimens. Functionally, promoted proliferation Warburg effect (aerobic glycolysis) cells. Mechanistically, harbor miR-487a, acting as miRNA sponge, then miR-487a targeted 3’-UTR hypoxia-inducible factor-1α (HIF-1α). Moreover, HIF-1α could bind with promoter hexokinase II (HK2) transcription. In conclusion, this finding illustrates vital roles via circRNF20/ miR-487a/HIF-1α/HK2 axis progress effect, providing an interesting insight for

Language: Английский

---

Role of circular RNAs in brain development and CNS diseases

Progress in Neurobiology, Journal Year: 2020, Volume and Issue: 186, P. 101746 - 101746

Published: Jan. 10, 2020

Language: Английский

---

Paving the Road for RNA Therapeutics

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(10), P. 755 - 775

Published: Sept. 3, 2020

Language: Английский

---

Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease

Circulation Research, Journal Year: 2020, Volume and Issue: 126(5), P. 663 - 678

Published: Feb. 27, 2020

RNA modulation has become a promising therapeutic approach for the treatment of several types disease. The emerging field noncoding RNA-based therapies now come to attention cardiovascular research, in which it could provide valuable advancements comparison current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on studies conducted mainly large-animal models, including pigs, rabbits, dogs, and nonhuman primates. obstacles promises targeting long RNAs circRNAs modalities humans are specifically discussed. We also describe novel ex vivo methods based human cells tissues, engineered heart tissues living myocardial slices that help bridging gap between models clinical applications future. Finally, summarize antisense oligonucleotide have already been approved by Food Drug Administration mRNAs discuss progress trials. Additional factors, drug chemistry, formulations, different routes administration, advantages drugs, included present review. Recently, first miRNA-based inhibitory strategies tested failure patients well healthy volunteers study effects wound healing (NCT04045405; NCT03603431). summary, combination targets, with cells/tissues, new delivery techniques will likely lead significant development next-generation therapeutics

Language: Английский

---

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Cancers, Journal Year: 2019, Volume and Issue: 11(2), P. 194 - 194

Published: Feb. 7, 2019

Circular RNAs are a large group of whose cellular functions still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation physical interaction between SRFS1 circSMARCA5, we assayed real-time PCR cohort 31 GBM biopsies 20 unaffected brain parenchyma controls (UC) expression total, pro-angiogenic (Iso8a) anti-angiogenic (Iso8b) mRNA isoforms Vascular Endothelial Growth A (VEGFA), known target SRSF1. The Iso8a to Iso8b ratio: (i) increased with respect UC (p-value < 0.00001); (ii) negatively correlated (r-value = −0.46, p-value 0.006); (iii) decreased U87-MG overexpressing negative control 0.0055). Blood vascular microvessel density, estimated within same biopsies, −0.59, 0.00001), while positively SRSF1 0.38, 0.00663) ratio 0.41, 0.0259). Kaplan-Meier survival analysis showed patients low had lower overall progression free rates than those higher (p-values 0.033, 0.012, respectively). Our data convincingly suggest is an upstream regulator pro- VEGFA cells highly promising prognostic prospective molecule.

Language: Английский

---

CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: March 12, 2020

Abstract Background Aberrant expression of circular RNAs contributes to the initiation and progression cancers, but underlying mechanism remains elusive. Methods RNA-seq qRT-PCR were performed screen differential expressed circRNAs between gastric cancer tissues adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out validated by qRT-PCR. Cell proliferation invasion ability determined CCK-8 cell assays. RNA-seq, GO-pathway, RNA pull-down ChIRP further applied search for detailed mechanism. Results Here, a novel named circMRPS35, in tissues, whose is related clinicopathological characteristics prognosis patients. Biologically, circMRPS35 suppresses cells vitro vivo. Mechanistically, acts as modular scaffold recruit histone acetyltransferase KAT7 promoters FOXO1 FOXO3a genes, which elicits acetylation H4K5 their promoters. Particularly, specifically binds FOXO1/3a promoter regions directly. Thus, it dramatically activates transcription triggers subsequent response downstream target genes expression, including p21, p27, Twist1 E-cadherin, resulting inhibition invasion. Moreover, positively correlates with that Conclusions Our findings not only reveal pivotal roles governing modification anticancer treatment, also advocate triggering circMRPS35/KAT7/FOXO1/3a pathway combat cancer.

Language: Английский

---

Exosomal circRNA: emerging insights into cancer progression and clinical application potential

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: June 26, 2023

Abstract Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune fibroblasts, other components, thereby regulating critical aspects of cancer progression including escape, angiogenesis, metabolism, drug resistance, proliferation metastasis. Interestingly, microenvironment have new findings in influencing escape mediated by the release exosomal circRNA. Given intrinsic stability, abundance, broad distribution circRNAs, they represent excellent diagnostic prognostic biomarkers for liquid biopsy. Moreover, artificially synthesized circRNAs may open up possibilities therapy, potentially bolstered nanoparticles or plant exosome delivery strategies. In this review, we summarize functions underlying mechanisms cell non-tumor cell-derived progression, with special focus on their roles immunity metabolism. Finally, examine potential application therapeutic targets, highlighting promise clinical use.

Language: Английский

---