The 1918 Influenza A Pandemic
Patricia G. Melloy in Viruses and Society, 2023
Influenza belongs to the family of viruses known as Orthomyxoviridae (Orthomyxoviruses). Members of this viral family are characterized by a segmented genome made of negative-sense single-stranded RNA. (A negative-sense RNA strand is the antisense strand, the opposite of what would code for mRNA.) Orthomyxoviruses can infect a wide range of species (Lostroh 2019; Couch 1996; Ackermann, Berthiaume, and Tremblay 1998). Influenza viruses have been found in birds, pigs, horses, seals, mink, and whales, in addition to humans (Webster et al. 1992). A translation of the term “orthomyxoviruses” indicates that this is a “straight-mucus family of viruses” (Brown 2018). Using the Baltimore classification system, influenza A would be a member of Class V, based on its genome type (Baltimore 1971).
Gene Therapy for Lung Cancer
Kenneth L. Brigham in Gene Therapy for Diseases of the Lung, 2020
Several antisense approaches have been investigated. One approach is through the use of antisense oligonucleotides, in which the phosphodiester backbone is modified to methylphosphonate or phosphorothioate to reduce degradation by nucleases. These modified antisense oligonucleotides can enter tumor cells by endocytosis and form DNA-RNA duplexes with endogenous sense mRNA, inhibiting translation. Another approach to inactivating mRNA is via ribozymes. Ribozymes are essentially antisense oligonucleotides that contain RNase active sites. A ribozyme possessing this activity allows catalytic gene ablation by sequence-specific cleavage of the target transcript. A third approach is to use plasmids or viral vectors for transferring an open reading frame fragment of the desired gene oriented backwards (3' to 5') behind a powerful promoter, resulting in the production of an antisense RNA. Antisense RNA transcribed from these constructs form a RNA duplex with sense mRNA inhibiting translation (89).
siRNA Delivery for Therapeutic Applications Using Nanoparticles
Yashwant Pathak in Gene Delivery, 2022
Conjugation of small molecules, such as peptides or polymers, with the sense strands of siRNA produces the smallest siRNA nanoparticles at 10 nm size [11]. Modification of sense strands of siRNA maintain the degradation effect on mRNA because the recognition of mRNA involves the antisense strand. Studies show that siRNA conjugation with CPPs and PEG has increased gene transfer in vivo. siRNA conjugated to cholesterol in sense strand are able to slice multiple genes in mice, including endogenous apolipoprotein B gene expression in the liver and jejunum and p38 mitogen-activated protein (MAP) kinase in the lungs [12]. In vivo gene silencing to hepatocytes was observed by siRNA modified with Long chain fatty acids (> C18) and bile-salt derivatives. A similar effect was also produced by siRNA based dynamic polyconjugate, consisting of acid responsive polymers that contain PEG and a NAG targeting ligand. When these nanoparticles interact with the endosome, PEG is released due to acid responsive polymer targeting the ligand, making a hydrophilic to hydrophobic transition, and resulting in endosomal disruption [13, 14, 15].
Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia
Published in Expert Opinion on Drug Safety, 2022
Yajnavalka Banerjee, Anca Pantea Stoian, Arrigo Francesco Giuseppe Cicero, Federica Fogacci, Dragana Nikolic, Alexandros Sachinidis, Ali A. Rizvi, Andrej Janez, Manfredi Rizzo
siRNAs are small dsRNAs (19–25 bp) that do not code to translate any molecule; they are significant mediators of the RNAi process, representing a novel therapeutic platform to exploit the natural mechanism of RNAi to inhibit protein synthesis. They are exogenously transfected into the cell and further incorporated into the RNAi machinery. Long dsRNAs, transfected in low concentrations to avoid immune response through the activation of the interferon pathway, are cleaved by Dicer, which is a dsRNA-specific ribonuclease, into 21–25 nucleotide-long ds siRNAs with two nucleotides in their 3ʹ overhang and 5ʹ phosphate groups. siRNAs are further recognized by the Argonaute 2 (AGO2) (a protein with a key role in RNA silencing) and RNA-induced silencing complex (RISC) (a multiribonucleoprotein complex) and unwind into their single-strand components [21–23]. The sense strand is degraded, and its complement-antisense strand binds via nucleotide complementarity targeting mRNA sequence. This is cleaved by AGO2 and degraded by exonucleases [24,25]. The result of such an association is solely dependent on the complementarity between siRNA and the target gene [26]. Although siRNAs have a specific target gene, they can also knock down unintended genes in two ways: (1) either deficient complementarity to non-targeted mRNAs or (2) by entering the endogenous miRNA machinery [26].
Developments in pharmacotherapeutic agents for hepatitis B – how close are we to a functional cure?
Published in Expert Opinion on Pharmacotherapy, 2023
Naoshin Khan, Mohamed Ramzi Almajed, Mary Grace Fitzmaurice, Syed-Mohammed Jafri
siRNAs are considered translation inhibitors that bind to HBV mRNA, preventing virion production. siRNA is typically conjugated with N-acetylgalactosamine to increase hepatocellular uptake [75]. Both ASOs and siRNAs act by silencing gene expression at the level of HBV mRNA. ASOs consist of a single-stranded antisense oligonucleotide that directly binds sense mRNA strands to exert its action. siRNAs consist of a small RNA duplex that loses a passenger strand to allow a guide strand to associate with RNA-induced silencing complex where it exerts its action [76]. Current siRNAs including JNJ-3989, VIR-2218, RG-6346, and AB-729 have resulted in marked decline of HBsAg months after treatment as demonstrated in phase I studies of combined therapy with siRNA and NA [77]. However, HBsAg levels did not change after 16–20 weeks despite 48 weeks of total treatment [78]. With agents such as AB-729 (currently in phase II of development), some patients developed upregulation of HBV-specific T-cell activation markers in the setting of decreased HBsAg levels and modest ALT flares [79]. This further demonstrates the role of combination therapy. Currently, a phase II study through VIR Biotech evaluating VIR-2218 in conjunction with PEG-IFNa and NA has shown marked HBsAg reduction with 3 log10 IU/ml decrease in comparison to 1.5 log IU/ml with VIR-2218 alone [80]. Therefore, future studies would benefit from combined therapies in further reducing HBsAg levels with the prospect of HBsAg loss.
The potential of BRAF-associated non-coding RNA as a therapeutic target in melanoma
Published in Expert Opinion on Therapeutic Targets, 2019
Luigi Fattore, Rita Mancini, Paolo Antonio Ascierto, Gennaro Ciliberto
For example, sense lncRNAs are transcribed from the same DNA strand of coding genes and contain exons whereas, in contrast, antisense lncRNAs are encoded from the antisense strand of protein-coding genes [40]. Furthermore, since those molecules are located within different genomic loci, they may be transcribed from regions located between genes and are so named intergenic lncRNAs whereas others derive entirely from introns and are then called intronic lncRNAs [40]. Another class, namely pseudogenes, such as KRASP1 (KRAS Proto-Oncogene, GTPase Pseudogene 1) and PTENP1 (Phosphatase And Tensin Homolog Pseudogene 1), are pseudogenes of the oncogene KRAS; they can act as sponges for miRNAs to stabilize their homologous mRNAs [40]. lncRNAs are able to affect gene expression at multiple levels and by mechanisms of action they are currently divided into four types: signal lncRNA, decoy lncRNA, guide lncRNA, and scaffold lncRNA [40] (Figure 2(c)).
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