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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)
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 potential role of miRNAs in multiple myeloma therapy
Published in Expert Review of Hematology, 2018
Daniele Caracciolo, Martina Montesano, Emanuela Altomare, Francesca Scionti, Maria Teresa Di Martino, Pierosandro Tagliaferri, Pierfrancesco Tassone
miRNA-based therapeutic strategies are evaluated in several clinical trials for the treatment of different disease, including cancer [24]. The first miRNA-based therapeutic named Miravirsen (SPC3649), reached phase II clinical trials for the treatment of hepatitis C virus (HCV) infection. Miravirsen is an LNA-ASOs which blocks miR-122 interaction with HCV RNA; thus, promoting virus destruction [25].
miRNAs as attractive diagnostic and therapeutic targets for Familial Mediterranean Fever
Published in Modern Rheumatology, 2021
Hamza Malik Okuyan, Mehmet A. Begen
Considering the upregulation or downregulation of miRNA expressions with the approaches mentioned above, such as Antagomirs and mimics use, research laboratories and biotech companies have focused on developing miRNA-based therapeutics in recent years [82]. The studies on miRNA-based therapeutics with some successful trials present promising approaches for treating diseases [82]. However, some miRNA-based therapeutics are now at a clinical development stage, and none are yet used in clinical settings for therapeutic purposes [88]. Some miRNA-based drugs are shown to have substantial efficacy in several pathological conditions such as hepatitis C, cancer, and fibrosis in preclinical, clinical phases 1 and 2 [82,88]. miR-122 increases the stability of the hepatitis C virus (HCV) RNA genome by binding 5ʹ end of the non-coding region of the viral RNA, thereby promotes the replication of the HCV genome in liver tissue [89]. Previous in vivo studies reported that miR-122-targeted therapy decreased HCV infection's viral capacity [90,91]. Miravirsen (or SPC3649), the first one of the miRNA-based therapeutics candidates developed by Santaris Pharma, is an antagomir targeting miR-122 designed by chemically LNA technology. miR-122 activity and viral titre of the HCV were suppressed after administration of Miravirsen into patients with HCV in the phase II trials (clinicalTrials.gov, NCT01200420), suggesting that Miravirsen have therapeutic antiviral efficiency [92]. miR-155, implicated in the differentiation and proliferation processes, is upregulated in blood cancer such as leukemia and lymphoma [93]. Babar et al. reported that suppression of miR-155 might have therapeutic activity in the mouse model of lymphoma [94]. Cobomarsen, also known as an MRG-106, is an LNA-based antagomiR developed by MiRagen therapeutics to suppress miR-155 and is still involved in phase 1 and phase 2 (respectively, clinicalTrials.gov, NCT02580552 and NCT03713320) [93]. miR-29 acts as a regulator of the genes which contribute to extracellular matrix deposition, and the downregulation of miR-29 in fibroblasts cause pathological fibrosis by enhancing the expressions of the collagens [95]. Montgomery et al. revealed that intravenously administering miR-29 mimics has a protective effect against pulmonary fibrosis by reducing collagen synthesis in a mouse model [96], suggesting that miR-29 could be a potential therapeutic target in fibrosis-related diseases [97]. MRG‑201 mimics developed by miRagen Therapeutics to restore decreased miR-29 expressions in fibrotic diseases is a promising example of miRNA replacement therapy, and phase II trial of MRG-201 is still ongoing (ClinicalTrials.gov, NCT03601052) in patients with systemic sclerosis [98].