<i>In Vitro</i>
            Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122

Ottosen, Søren; Parsley, Todd B.; Yang, Lu; Zeh, Karin; Doorn, Leen–Jan van; Veer, Eva van der; Raney, Anneke K.; Hodges, Michael R.; Patick, Amy K.

doi:10.1128/aac.04220-14

Cited by 191 publications

(141 citation statements)

References 42 publications

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“…Previously, we discovered that introducing mutations in S1 or substituting both SLI and S1 with a host U3 snoRNA fragment conferred virus resistance to miravirsen treatment (Li et al, 2011a), thus indicating that virus escape could potentially occur in HCV patients during miravirsen-based therapy. Recently, HCV rebound in an HCV patient observed after completion of miravirsen clinical phase II trial was found to be associated with mutation C3U in the 5¢E involved in miR-122 binding (Ottosen et al, 2015). However, this finding could not be confirmed in vitro, as the 5¢E_C3U virus reverted to the WT sequence in our study (Table 1).…”

Section: Discussioncontrasting

confidence: 55%

“…We demonstrated previously that introduction of selected mutations in the miR-122 binding site S1 conferred virus resistance to miravirsen treatment in cell culture (Li et al, 2011a); subsequent studies identified virus resistant to miravirsen treatment (Israelow et al, 2014;Ottosen et al, 2015). These observations indicate that HCV therapy using miR-122 antagomirs would also encounter the issue of virus escape.…”

Section: Introductionmentioning

confidence: 90%

“…Miravirsen has demonstrated broad antiviral activity against various genotypes of HCV (Li et al, 2011a), and no evidence of virus resistance was originally identified in HCV-infected chimpanzees after miravirsen treatment (Lanford et al, 2010) or in patients in clinical phase II trials (Janssen et al, 2013). As mentioned above, the 5¢E mutation C3U emerged in a miravirsen-treated HCV patient, but the virus was still fully susceptible to other direct-acting agents (DAAs) (Ottosen et al, 2015); thus, HCV that escaped from miravirsen treatment could be treated by DAAs. This observation suggests that a combination of miravirsen and DAAs may create a higher genetic barrier preventing virus escape from treatment.…”

Section: Discussionmentioning

confidence: 99%

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Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

Pham

Uzcátegui

et al. 2016

Journal of General Virology

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MicroRNA 122 (miR-122) stimulates the replication and translation of hepatitis C virus (HCV) RNA by binding to two adjacent sites, S1 and S2, within the HCV 5¢UTR. We demonstrated previously that the miR-122 antagomir miravirsen (SPC3649) suppresses the infection of HCV strain JFH1-based recombinants with HCV genotypes 1-6 5¢UTR-NS2 in human hepatoma Huh7.5 cells. However, specific S1 mutations were permitted and conferred virus resistance to miravirsen treatment. Here, using the J6 (genotype 2a) 5¢UTR-NS2 JFH1-based recombinant, we performed reverse-genetics analysis of S1 (ACACUCCG, corresponding to miR-122 seed nucleotide positions 8-1), S2 (CACUCC, positions 7-2), and ACCC (positions 1-4) at the 5¢ end of the HCV genome (5¢E); the CC at positions 2-3 of 5¢E is involved in miR-122 binding. We demonstrated that the 5¢E required four nucleotides for optimal function, and that G or A at position 3 or combined GA at positions 2-3 of 5¢E was permitted. In S1 and S2, several single mutations were allowed at specific positions. A UCC fi CGA change at positions 4-3-2 of S1, S2, or both S1 and S2 (S1/S2), as well as a C fi G change at position 2 of S1/S2 were permitted. We found that 5¢E mutations did not confer virus resistance to miravirsen treatment. However, mutations in S1 and S2 induced virus resistance, and combined S1 and/or S2 mutations conferred higher resistance than single mutations. Identification of miR-122 antagomir resistance-associated mutations will facilitate the study of additional functions of miR-122 in the HCV life cycle and the mechanism of virus escape to host-targeting antiviral approaches.

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Section: Discussioncontrasting

confidence: 55%

Section: Introductionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

Pham

Uzcátegui

et al. 2016

Journal of General Virology

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“…Antisense technology also has proven successful in blocking miRNA activity: synthetic oligonucleotides of different chemistries targeted to known oncogenic miRNAs, such as miR-17, miR-21, miR-155, and miR-221/222 promoted not only induction of apoptosis and inhibition of proliferation, but also tumour regression and metastasis suppression in vivo [32][33][34][35][36][37][38]. The drugs Miravirsen and Regulus RG-101, aimed at suppressing miRNA-122 for the treatment of hepatitis C, have successfully progressed into clinical trials, and thus provide grounds to believe that, in the near future, effective antisense-based anti-miRNA therapies will be developed to combat oncopathology [39,40].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

et al. 2017

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Please cite this article as: Patutina OA, Bichenkova EV, Miroshnichenko SK, Mironova NL, Trivoluzzi LT, Burusco KK, Bryce RA, Vlassov VV, Zenkova MA, miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells, Biomaterials (2017Biomaterials ( ), doi: 10.1016Biomaterials ( / j.biomaterials.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…[58][59][60][61][62] A combination approach has also been proposed for the treatment of hepatitis C virus infection through the use of antiviral drugs (telaprevir and ribavirin) with miRNA-based therapy (miravirsen, ClinicalTrials identifier NCT01872936). 63 Similarly, since hepatitis B virus affects miRNA cellular levels in several ways, new miRNA-based approaches could represent a promising area of investigation for treatment of hepatitis B virus infection and reduction of the risk of HCC.…”

Section: Mirnas As Therapeutic Agentsmentioning

confidence: 99%

Emerging role of microRNAs in the treatment of hepatocellular carcinoma

Callegari¹,

Domenicali²,

Gramantieri³

et al. 2015

GICTT

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Hepatocellular carcinoma is the third leading cause of cancer deaths worldwide. Currently available curative options, such as surgery and transplantation, are not available to patients with advanced stages of disease. Among the potential new treatments being investigated are microRNA (miRNA)-based therapies. A number of preclinical studies have reported antitumor activities of miRNA mimics or anti-miRNA molecules. Optimal in vivo delivery of miRNA molecules is crucial to their action. To this end, significant progress has been made in the development of nanoparticles for in vivo delivery of miRNA molecules. Delivery of these molecules, alone or in combination with other drugs, promises to open new possibilities for therapeutic approaches to hepatocellular carcinoma.

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In Vitro Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122

Cited by 191 publications

References 42 publications

Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

Emerging role of microRNAs in the treatment of hepatocellular carcinoma

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