China
Africa
Explore chapters and articles related to this topic
Investigational Antiviral Drugs
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
John Mills, Suzanne M. Crowe, Marianne Martinello
Miravirsen (SPC3649) is unique. It is a modified oligonucleotide that antagonizes the liver-expressed micro-RNA (miR-122). Propagation of HCV depends on a functional interaction between the HCV genome and the liver-expressed miR-122; miravirsen sequesters mature miR-122 in a highly stable heteroduplex, thereby disrupting that dependency. Because miravirsen is an oligonucleotide, not absorbed orally, it is formulated for subcutaneous injection. A phase IIa randomized, double-blind, placebo-controlled, ascending multiple dose-ranging study enrolled 36 subjects with chronic HCV GT-1 between September 2010 and November 2011 who were given 5 weekly injections of miravirsen for 4 weeks at doses of 3, 5, or 7 μg; treatment with miravirsen resulted in prolonged dose-dependent reduction in HCV RNA by 1.2 to 3.2 log10 as compared with placebo (–0.4 log10). As compared with placebo, participants receiving miravirsen reported no significant dose-related adverse reactions, and there was no evidence of resistant virus appearing (Janssen et al., 2013; van der Ree et al., 2014; Li et al., 2016; Ottosen et al., 2015; van der Ree et al., 2014; van der Ree et al., 2016)
Determination of Toxicity
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Research into markers of effect has blossomed in recent years. In early experiments, effects were marked by relatively crude endpoints such as death, exclusion of dyes, or leakage of simple markers such as lactate dehydrogenase. However, there has been much evolution in the sophistication of markers of effect in recent years. Godoy et al. (2013) reported that microRNAs, which are RNA of 19 to 25 nucleotides, which do not code, have been shown to play a major role in regulating gene expression, and cell differentiation and replication. Aberrant expression of microRNAs has been associated with different cancers. In addition, they are tissue specific; for example, miR-122 accounts for approximately 70% of all hepatic miRNA and has wide-ranging effects, offering much utility as a marker of change in the liver.
Mechanisms of Hepatitis C Virus Clearance by Interferon and Ribavirin Combination
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Srikanta Dash, Partha K. Chandra, Kurt Ramazan, Robert F. Garry, Luis A. Balart
Two classes of small RNA–based antiviral approaches—called small interfering RNAs (siRNAs) and microRNAs (miRNAs)—have been developed. Some of the anti-HCV strategies using small RNAs (siRNA and miRNA) have shown promising results in the cell culture, animal models, and clinical trials. Small RNAs are the specificity components of a protein machinery called RNA-induced silencing complex (RISC) that uses the small RNAs to recognize complementary motifs in target nucleic acids and degrades the target RNA using a specific silencing mechanism. HCV is an RNA virus that replicates in the cytoplasm inhibition of HCV replication by intracellular delivery of siRNA or miRNA to offer an alternative intracellular therapeutic approach. These small RNAs can be used as powerful antivirals against a number of viruses that cannot be cleared by small- molecule drugs. The miRNA-122 has been shown to modulate HCV replication by binding to the 5′-UTR of HCV genome (Joplin et al. 2005). It has been shown that miRNA-122 antagonist reduces HCV titers in HCV-infected chimpanzees (Lanford et al. 2010). Recent clinical studies show that antisense oligonucleotide miravirsen, which binds to miRNA-122, has no adverse events and inhibits chronic HCV infection in humans; thus, it is the best candidate to be licensed to use in the clinic. Phase II clinical studies using miRNA-122 show a great promise as a molecular approach to hepatitis C treatment in humans (Janssen et al. 2013). Another proof of principle study performed in our laboratory shows that intracellular delivery of a combination of two siRNAs targeted to the HCV 5′-UTR minimizes escape mutant viruses and leads to rapid inhibition of HCV replication in cell culture and in an animal model (Chandra et al. 2012). These studies provide a hope for development of alternative therapies for drug-resistant HCV in the future.
Current progress of miRNA-derivative nucleotide drugs: modifications, delivery systems, applications
Published in Expert Opinion on Drug Delivery, 2022
Charles Asakiya, Liye Zhu, Jieyu Yuhan, Longjiao Zhu, Kunlun Huang, Wentao Xu
After mdCNDs enter into the cell, it will bind with target genes to active or inhibit the downstream pathway to improve the disease. However, the degradation of miRNA in cell is still not clear. The most recent searchable databases of mdCNDs undergoing clinical trials are available on clinicaltrials.gov, clinicaltrialsregister.eu, and research.cicc.com. These databases have reported over 15 mdCNDs in various phases of clinical development. Miravirsen is the first mdCNDs to advance through clinical trials in hepatic virus C (HCV) infected patients (NCT01200420)[9]. MiR-122 is implicated in the liver, a significant therapeutic target for treating liver diseases since miR-122 expressions are reduced in the liver[10]. MRX34, a tumor suppressor miR-34a mimics, is the first mdCNDs to enter clinical trials (NCT01829971). However, the experiment has been terminated due to the sponsor’s decision[11]. mdCNDs exert their therapeutic functions in two strategies, either working as a replacement strategy where tumor-suppressor miRNA mimics reinstates their loss of function or as oncogenic inhibitors. Although mdCNDs are implicated in various diseases, their development into clinical drugs is vague despite their high-potential drug targets. Due to the high cost of developing new drugs, much attention has been drawn to miRNAs. This chapter provides the current status of mdCNDs undergoing clinical trials.
The Relationship between Extracellular/intracellular microRNAs and TLRs May Be Used as a Diagnostic and Therapeutic Approach in Sepsis
Published in Immunological Investigations, 2022
Navid Shomali, Ata Mahmoodpoor, Ali Namvaran Abbas Abad, Faroogh Marofi, Morteza Akbari, Huaxi Xu, Siamak Sandoghchian Shotorbani
miR-122 is a liver-specific microRNA that is abundant in liver cells. High levels of miR-122-rich exosomes have been reported to be present in the sera of patients with sepsis. Moreover, miR-122-enriched exosomes can be transferred to monocytes. By sensitizing these microRNAs with LPS, they cause increased inflammation (Rahmel et al. 2018). Recent studies have shown an association between TLR14 and miR-122, in which TLR14 expression promotes the activation of AP-1 and NF-KB by miR-122 transcription, which could negatively regulate the TLR14 targets. miR-122 has been shown to be involved in altering the function of TLRs to induce nuclear factor-κB signals (Wang et al. 2014a). The results of a study revealed that miR-122 is dysregulated in patients with sepsis (David et al. 2017). Moreover, the diagnostic value of miR-122 in sepsis was reported recently (Giza et al. 2016b). Microbial infections lead to the expression of specific cardiac complement factor B in vivo, in which it was shown that miR-122 re-expression induced the production of complement factor B (CFB) in macrophages by the TLR7-MyD88-dependent method. This shows the participation of miR-122 in sepsis pathogenesis (Zou et al. 2016).
Serum MicroRNA on inflammation: a literature review of mouse model studies
Published in Biomarkers, 2020
In most studies, miRNAs significantly affected pro- or anti-inflammation, such as protecting cells from inflammation triggers and regulating immune cells and molecular mediators. Studies showed various changes of microRNA and their underlying mechanisms associated in inflammatory processes. Among them, miR-155 and miR-122 have been shown up mostly in inflammation studies. miR-155 is stimulated by TNF-α to target sirtuin1 (SIRT1), regulates endothelial senescence (Guo et al.2019), and transfuses into wild-type macrophage (Wang et al.2017). This microRNA activates macrophages and dendritic cells regulating secretion of inflammatory cytokines (Mashima 2015). miR-122 is decreased under hepatocellular carcinoma or hepatitis C virus replication, and it induces anti-viral genes regulating IFN signalling pathway (Narbus et al.2011). Also, miR-122 regulates liver inflammation in NAFLD (Jampoka et al.2018) and cellular interactions including mast cells and macrophages are regulated via miR-122/SOCS1/JAK2 pathway (Noh et al.2017). Based on these reports, miR-155 shows a wide association with inflammatory genes in macrophage and cytokine secretion, miR-122 have a main function in hepatic regulation and its inflammatory dysfunction. Still there is a missing link to figure the whole function of these miRNAs, serum miR-155 and miR-122 might play a role as biomarkers in inflammatory diseases.