Sequence 774 (Miravirsen , SPC3649)

Sequence Miravirsen , SPC3649
Target	miR-122 ( Homo sapiens )
Description	miR122
Design	LNA mixmer
Chemistry	+C*C*+A*T*T*+G*+T*C*A*+C*A*+C*T*+C*+C
Sequence	CCATTGTCACACTCC
Application	gene silencing
Name	Miravirsen , SPC3649

References

Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Gebert LF, Rebhan MA, Crivelli SE, Denzler R, Stoffel M, Hall J. Nucleic Acids Res. 2014 Jan;42(1):609-21.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Background

Gene Function. Jopling et al. (2005) found that sequestration of miR122 in liver cells resulted in marked loss of autonomously replicating hepatitis C virus (HCV; see 609532) RNAs. Mutational analysis revealed a genetic interaction between miR122 and the 5-prime noncoding region of the HCV genome, but the interaction did not impair mRNA translation or RNA stability. Jopling et al. (2005) concluded that miR122 is likely to facilitate replication of HCV RNA and proposed that miR122 may be a target for antiviral intervention.

Using microarray, PCR, and complementarity analyses, Pedersen et al. (2007) identified 8 miRNAs that were rapidly upregulated in IFNB (IFNB1; 147640)-stimulated mouse and human liver cell lines that showed sequence complementarity to HCV, an RNA virus, but not to hepatitis B virus (HBV; see 610424), a DNA virus. Of the 8 upregulated miRNAs, miR196 (MIRN196; 608632), miR296 (MIRN296; 610945), miR351 (MIRN351), miR431 (MIRN431; 611708), and miR448 (MIRN448; 300686) had anti-HCV activity, and miR196 and miR448 directly targeted HCV genomic RNA. IFNB stimulation downregulated miR122, a liver-specific miRNA essential for HCV replication. Pedersen et al. (2007) concluded that IFNA (IFNA1; 147660) and IFNB, a common treatment regimen for HCV infection, use cellular miRNA, at least in part, to combat viral infections.

Czech (2006) discussed the clinical implications of the study of Krutzfeldt et al. (2005), which showed that inhibition of the liver-specific microRNA miR122 could be therapeutic in mice. Using a pharmacologic approach, Krutzfeldt et al. (2005) synthesized single-stranded 23-nucleotide RNA molecules complementary to the targeted miR122 in such a way as to stabilize the RNA and protect it from degradation. Next, the stabilized 23-mer RNAs were covalently linked to cholesterol molecules, aiding their delivery into liver cells. On injection of these cholesterol-conjugated RNA molecules, termed 'antagomirs,' into the tail veins of mice, efficient and specific ablation of the targeted endogenous miR122 was observed. The widespread silencing of miR122 produced a 44% decrease in plasma cholesterol levels. Silencing of the miR122 resulted in an increase in expression of several hundred genes, including those that are normally repressed in hepatocytes. The last finding indicated that miR122 may help maintain the adult-liver phenotype by suppressing 'nonliver' genes. As expected, many of these genes contain a miR122 recognition sequence in their 3-prime untranslated regions and therefore can be bound directly by miR122 and disabled.

Bhattacharyya et al. (2006) found that endogenous cationic amino acid transporter-1 (CAT1, or SLC7A1; 104615) mRNA was translationally repressed by miR122 in Huh7 human hepatoma cells. CAT1 mRNA and reporters bearing its 3-prime UTR could be relieved from miR122-mediated repression by subjecting Huh7 cells to different stress conditions. This derepression was accompanied by release of CAT1 mRNA from cytoplasmic processing bodies and its entry into polysomes, and this process involved binding of HuR (ELAVL1; 603466) to the 3-prime UTR of CAT1.

Using microarray, Northern blot, and RT-PCR analyses, Gramantieri et al. (2007) found that expression of miR122A was downregulated in about 70% of hepatocellular carcinomas (HCCs) from cirrhotic livers and in all HCC-derived cell lines examined. miR122A modulated cyclin G1 (CCNG1; 601578) expression in HCC-derived cell lines, and an inverse correlation between miR122A and cyclin G1 expression was observed in primary liver carcinomas. Using the putative miR122A target sequence from the 3-prime UTR of cyclin G1 coupled to a reporter gene, Gramantieri et al. (2007) confirmed that miR122A directly controlled expression of cyclin G1.

Elmen et al. (2008) demonstrated that the simple systemic delivery of an unconjugated PBS-formulated locked-nucleic-acid-modified oligonucleotide, LNA-antimiR, effectively antagonizes the liver-expressed miR-122 in nonhuman primates. Acute administration by intravenous injections of 3 or 10 mg/kg LNA-antimiR to African green monkeys resulted in uptake of the LNA-antimiR in the cytoplasm of primate hepatocytes and formation of stable heteroduplexes between the LNA-antimiR and miR-122. This was accompanied by depletion of mature miR-122 and dose-dependent lowering of plasma cholesterol. Efficient silencing of miR-122 was achieved in primates by 3 doses of 10 mg/kg LNA-antimiR, leading to a long-lasting and reversible decrease in total plasma cholesterol without any evidence of LNA-associated toxicities or histopathologic changes in the study animals. Elmen et al. (2008) concluded that their findings demonstrated the utility of systemically administered LNA-antimiRs in exploring miRNA function in rodents and primates, and supported the potential of these compounds as a new class of therapeutics for disease-associated miRNAs.

Lanford et al. (2010) found that treatment of chronically infected chimpanzees with a locked nucleic acid-modified oligonucleotide complementary to miR122 leads to long-lasting suppression of hepatitis C (HCV) viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histologic analyses of liver biopsies demonstrated derepression of target mRNAs with miR122 seed sites, downregulation of interferon (see 147660)-regulated genes, and improvement of HCV-induced liver pathology. Lanford et al. (2010) suggested that prolonged virologic response to this agent without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.

Burns et al. (2011) showed that depletion of GLD2, also known as PAPD4 (614121), promotes rather than inhibits p53 (191170) mRNA polyadenylation/translation, induces premature senescence, and enhances the stability of CPEB (607342) mRNA. The CPEB 3-prime UTR contains 2 miR122 binding sites that when deleted elevate mRNA translation, as did an antagomir of miR122. Although miR122 is thought to be liver-specific, it is present in primary fibroblasts and destabilized by GLD2 depletion. GLD4 (PAPD5; 605540), a second noncanonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner. Thus, Burns et al. (2011) concluded that translational regulation of p53 mRNA and cellular senescence is coordinated by GLD2/miR122/CPEB/GLD4.