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Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
Studies reported that the modification of mRNA with a combination of 2-thiouridine and 5-methylcytidine effectively reduced the immune stimulation through pattern recognition receptors, such as TLR3, TLR7, TLR8, and retinoic acid receptor responder protein 3 also known as RIG-I [2, 23]. In addition, the inclusion of pseudouridine in the mRNA (Ψ-mRNA) blocked activation of pattern recognition receptors18 and 2ʹ-5ʹ-oligoadenylate synthetase19. These modifications can also stabilize the mRNA against cleavage and ultimately increase expression rates [24]. A direct intramyocardial injection of vascular endothelial growth factor A (VEGF-A)-encoding modified mRNA (modRNA) complexed with RNAiMAX in myocardial infarction mice decreased the infract size and apoptotic cell frequency, as compared to the control group [3, 23, 24]. In another study, pulmonary surfactant associated protein deficient mice showed 0% survival by five days, whereas mice with administration of modified PSPB-encoding mRNA showed >80% survival by day 30 [3]. Luciferase mRNA successfully delivered into mice after intranasal administration in which mRNA made complex transfection reagent Stemfect or to a hydrophobic poly(β-amino ester) that had been coated with a positively charged lipid layer.[25, 26]. This complex also could express luciferase in the spleen after IV administration [3, 26].
Analysis of Small RNA Species: Phylogenetic Trends
Published in S. K. Dutta, DNA Systematics, 2019
Mirko Beljanski, Liliane Le Goff
Different biological activities of 7S RNA have been suggested. Thus, 7S RNA isolated from eye lens74 is capable of binding activated amino acids. This RNA, rich in GC pairs (G + C/A + U = 1,9), does not contain pseudouridine and differs from transfer RNA in its size and nucleotide composition. No further investigations have been carried out with this RNA to determine its participation in protein or peptide synthesis. Purified 7S RNA from chicken embryos plays a direct role in heart tissue differentiation and development.82,83 Since a portion of 7S RNA sequence is homologous to sequences at the origin of DNA replication, it was suggested that 7S RNA may play a role in DNA replication. This may be possible and it should be feasible to demonstrate experimentally whether or not before acting as primer 7S RNA undergoes degradation in order to furnish smaller molecules whose size range is similar to that of RNA primers.
Alliances: Knowledge infrastructures and precision medicine
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
In addition to genomics, the field of metabolomics has proven to be essential in the discovery of a clinical biomarker for personalized medicine. Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate, which improve the diagnosis of heart failure (Dunn et al., 2007).
Making COVID-19 mRNA vaccines accessible: challenges resolved
Published in Expert Review of Vaccines, 2022
The delivery and protection of the mRNA vaccine began resolution in the late 1990s when the US government embarked on a multibillion-dollar quest to find a vaccine to prevent HIV infections. The HIV vaccine had failed due to the destruction of the mRNA as a natural response of the body to protect against foreign RNA such as the viral RNAs. The destruction apparatus in the cells comprises toll-like receptors (TLRs) in the cytoplasm; the TLRs are a class of proteins that are single-pass membrane-spanning receptors usually expressed on sentinel cells, such as macrophages and dendritic cells that recognize the structurally conserved molecules derived from microbes, the antigens or in this case the RNA. To prevent destruction by TLRs, the mRNA sequences had to be modified to make them look more like endogenous mRNA. One such modification is that using pseudouridine in place of uridine in the mRNA improves stability and increases translational capability [14]. Incidentally, the name of the famous mRNA company Moderna comes from ‘modified RNA.’
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
For gene therapy, both DNA and RNA are known to stimulate the mammalian innate immune system through activation of various nucleic acid sensors including some TLRs. To date, 13 TLRs have been identified and 4 of them (TLR3 for double-stranded RNA, TLR7/8 for U-rich single-stranded RNA, and TLR9 for CpG DNA motif) are involved in recognition of nucleic acid sequences. IVT mRNAs were found to induce strong TNF-α response in dendritic cells [35], through the recognition by TLR3 [82]. Two other receptors, namely retinoic acid inducible gene 1 (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5), can also be stimulated by double-stranded mRNA to induce type I IFN via the IFN-regulatory factor 3 (IRF3)-dependent pathway [32]. Importantly, the use of modified nucleosides, including 2ʹ-O methyl nucleoside, for in vitro transcription has been shown to dramatically suppress TLR-mediated DC activation [35]. However, the effects of modified nucleosides on TLR-independent immune response are not clear yet. In summary, other modified nucleosides present in mammalian RNAs (such as pseudouridine, 2ʹ-thiouridine, 5-methylcytidine, 6-methyladenosine, inosine, and various 2ʹ-O-methylated nucleosides at the 5ʹ-terminal cap of mRNAs) could also be used for IVT mRNAs to suppress immune reaction [83].
Quantifying RNA modifications by mass spectrometry: a novel source of biomarkers in oncology
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Amandine Amalric, Amandine Bastide, Aurore Attina, Armelle Choquet, Jerome Vialaret, Sylvain Lehmann, Alexandre David, Christophe Hirtz
Despite a global up-regulation of nucleotide metabolism in cancer, not all nucleosides are more concentrated in the serum of cancer patients compared to controls. For example, the uridine serum level was decreased in colorectal cancer [29]. Uridine was also decreased in esophageal cancer patient serum [30], whereas cytidine was increased, as were two modified guanosines, N2,N2-dimethylguanosine (m2,2G) and m2G [30]. These nucleoside changes were detected by LC-MS/MS. Further variations in prostate cancer patient serum included increased inosine and reduced 5-methyluridine (m5U) [35]. MS also revealed that serum levels of pseudouridine were lower in lung cancer [33].