Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection

Lanford, Robert E.; Hildebrandt-Eriksen, Elisabeth S.; Petri, Andreas; Persson, Robert; Lindow, Morten; Munk, Martin E.; Kauppinen, Sakari; Ørum, Henrik

doi:10.1126/science.1178178

Cited by 1,539 publications

(1,224 citation statements)

References 22 publications

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“…The same optimized miR-122 LNA/DNA-PS AMO described above was studied for efficacy as an anti-HCV therapy. 7 HCV-infected chimpanzees were administered this AMO at a dose of 1 or 5 mg kg À1 with weekly intravenous injection for 12 weeks followed by a 17-week recovery period. HCV RNA levels dropped by as much as 400-fold in the high-dose cohort and remained suppressed by 10-fold 16 weeks after discontinuation of treatment.…”

Section: Inhibiting Mirna Function With Synthetic Oligonucleotides Dementioning

confidence: 99%

“…5 Recently, evidence has shown that miRNAs also have a role in viral infections, which include invoking an antiviral response; alternatively, the viruses themselves can encode miRNAs or regulate endogenous host miRNAs, which aid in the infection process. 6,7 There are currently 41000 putative miRNAs encoded in the human genome, and miRNAs are estimated to regulate up to 60% of protein-coding mammalian genes. 8 As the number of discovered miRNAs and their regulated targets continually increases, the biological importance of these small non-coding RNAs becomes more evident.…”

Section: Introductionmentioning

confidence: 99%

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Chemical modification and design of anti-miRNA oligonucleotides

2011

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Antisense techniques have been employed for over 30 years to suppress expression of target RNAs. Recently, microRNAs (miRNAs) have emerged as a new class of small, non-coding, regulatory RNA molecules that widely impact gene regulation, differentiation and disease states in both plants and animals. Antisense techniques that employ synthetic oligonucleotides have been used to study miRNA function and some of these compounds may have potential as novel drug candidates to intervene in diseases where miRNAs contribute to the underlying pathophysiology. Anti-miRNA oligonucleotides (AMOs) appear to work primarily through a steric blocking mechanism of action; these compounds are synthetic reverse complements that tightly bind and inactivate the miRNA. A variety of chemical modifications can be used to improve the performance and potency of AMOs. In general, modifications that confer nuclease stability and increase binding affinity improve AMO performance. Chemical modifications and/or certain structural features of the AMO may also facilitate invasion into the miRNA-induced silencing complex. In particular, it is essential that the AMO binds with high affinity to the miRNA 'seed region', which spans bases 2-8 from the 5¢-end of the miRNA.

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Section: Inhibiting Mirna Function With Synthetic Oligonucleotides Dementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemical modification and design of anti-miRNA oligonucleotides

2011

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“…As an example, anti-miR10b-mediated targeting of breast cancer lung metastases was successfully achieved by intravenous injection of cholesterolconjugated anti-miRs (Ma et al, 2010). Therapeutic silencing of miR-122 with locked nucleic acid-modified oligonucleotides led to a long-lasting suppression of HCV viremia and improved liver pathology (Lanford et al, 2010). In addition to targeting of oncogenic miRNAs, administration of miRNAs with tumor suppressor activity, such as miR-26a (Kota et al, 2009), let-7 and miR-34a, has been tested for therapeutic potential in vivo in lung cancer models.…”

Section: Targeting Liver Metastasis With Anti-mir-182mentioning

confidence: 99%

“…Conceivably, these can be used to negate the regulatory effects of 'oncogenic' miRNAs (Croce, 2009). MiRNA silencing has also been successfully explored in non-malignant conditions such as HCV viremia suppression by silencing miR-122 with chemically modified oligonucleotides (Lanford et al, 2010), the clinical application of which is highly anticipated.…”

Section: Introductionmentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

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Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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“…Treatment with LNA‐based anti‐miR‐122 oligonucleotides was able to suppress viremia and improve HCV‐induced liver pathology in chimpanzees, also without negative side effects 120. Subsequent studies resulted in the development of miravirsen, an LNA‐modified antisense oligonucleotide against miR‐122, which was the first miRNA‐targeting drug in clinical use.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

Harish²,

et al. 2016

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Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA‐based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA‐based therapies could provide a critical step forward in cancer treatment.

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Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection

Cited by 1,539 publications

References 22 publications

Chemical modification and design of anti-miRNA oligonucleotides

Chemical modification and design of anti-miRNA oligonucleotides

Efficient in vivo microRNA targeting of liver metastasis

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

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