Miravirsen
(Synonyms: SPC-3649) 目录号 : GC64487
Miravirsen (SPC-3649) 是一种 β-d-氧锁核酸修饰的硫代磷酸反义寡核苷酸，可抑制 miR-122 的生物合成。Miravirsen (SPC-3649) 用于 HCV 感染的研究。
Cas No.:1072874-90-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Miravirsen (SPC-3649), a β-d-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide, inhibit the biogenesis of miR-122. Miravirsen (SPC-3649) is used in the study for HCV infections[1].
Miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV RNA, its target sequence is also present in pri- and pre-miR-122[1]. Miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors[1].
[1]. Luca F R Gebert, et al. Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res. 2014 Jan;42(1):609-21.
| Cas No. | 1072874-90-8 | SDF | Download SDF |
| 别名 | SPC-3649 | ||
| 分子式 | 分子量 | 4967 | |
| 溶解度 | Water : 100 mg/mL (20.13 mM; Need ultrasonic) | 储存条件 | Store at -20°C, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.2013 mL | 1.0066 mL | 2.0133 mL |
| 5 mM | 0.0403 mL | 0.2013 mL | 0.4027 mL |
| 10 mM | 0.0201 mL | 0.1007 mL | 0.2013 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma
Aliment Pharmacol Ther 2016 Jan;43(1):102-13.PMID:26503793DOI:10.1111/apt.13432.
Background: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of Miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients. Aim: To assess the plasma level of various miRNAs in patients dosed with Miravirsen. Methods: We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) Miravirsen or placebo (n = 4) over a 4-week period in a double-blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with Miravirsen or placebo. Results: Median plasma miR-122 level at baseline in patients receiving Miravirsen was 3.9 × 10(3) compared to 1.3 × 10(4) copies/4 μL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with Miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR-210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period. Conclusions: We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with Miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122.
Miravirsen (SPC3649) can inhibit the biogenesis of miR-122
Nucleic Acids Res 2014 Jan;42(1):609-21.PMID:24068553DOI:10.1093/nar/gkt852.
MicroRNAs (miRNAs) are short noncoding RNAs, which bind to messenger RNAs and regulate protein expression. The biosynthesis of miRNAs includes two precursors, a primary miRNA transcript (pri-miRNA) and a shorter pre-miRNA, both of which carry a common stem-loop bearing the mature miRNA. MiR-122 is a liver-specific miRNA with an important role in the life cycle of hepatitis C virus (HCV). It is the target of Miravirsen (SPC3649), an antimiR drug candidate currently in clinical testing for treatment of HCV infections. Miravirsen is composed of locked nucleic acid (LNAs) ribonucleotides interspaced throughout a DNA phosphorothioate sequence complementary to mature miR-122. The LNA modifications endow the drug with high affinity for its target and provide resistance to nuclease degradation. While Miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV RNA, its target sequence is also present in pri- and pre-miR-122. Using new in vitro and cellular assays specifically developed to discover ligands that suppress biogenesis of miR-122, we show that Miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors. This inhibition may contribute to the pharmacological activity of the drug in man.
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
Antimicrob Agents Chemother 2015 Jan;59(1):599-608.PMID:25385103DOI:10.1128/AAC.04220-14.
Miravirsen is a β-D-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC50) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥ 297. Combination studies of Miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2'-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5' untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the Miravirsen EC50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5'UTR from subjects with viral rebound after the completion of therapy in a Miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to Miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to Miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, Miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with Miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420).
Roadmap of miR-122-related clinical application from bench to bedside
Expert Opin Investig Drugs 2014 Mar;23(3):347-55.PMID:24354366DOI:10.1517/13543784.2014.867327.
Introduction: microRNA (miRNA) regulates target gene expression to influence many physiological and pathophysiological processes. The liver-specific miRNA, miR-122, contributes to liver function and plays a very important role in hepatic diseases including the viral hepatitis C (HCV). For this reason, developing an miR-122-related clinical application could be very useful in managing or treating many hepatic disorders. Areas covered: This review introduces the basic concepts of miRNA and miR-122. It also discusses the possibility of miR-122 as a biomarker and summarizes the results of anti-miR-122 treatment from basic research to a Phase IIa clinical trial. Furthermore, the authors discuss the potential opportunities and challenges found in clinical trials with Miravirsen. Expert opinion: miR-122 may be a useful biomarker as both a diagnostic and prognostic tool. Furthermore, Miravirsen is a novel treatment with great potential for hepatic disease treatment, especially in HCV. However, there is certainly the need for future investigations to better determine whether miR-122 is really specific for liver. It is also important to elucidate whether miR-122 is actually specific for HCV genome and further investigate the therapeutic potential of Miravirsen. Only once these studies have been completed can anti-miR-122 treatment potentially enter the clinical practice.
Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients
Antiviral Res 2014 Nov;111:53-9.PMID:25218783DOI:10.1016/j.antiviral.2014.08.015.
Background and aims: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following Miravirsen dosing and to assess long-term safety in patients treated with Miravirsen. Methods: In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with Miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of Miravirsen or placebo dosing. Results: PR therapy was started in 14/36 patients of whom 12 had received Miravirsen. SVR was achieved in 7/12 patients previously dosed with Miravirsen. All patients dosed with 7mg/kg Miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications. Conclusion: No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.