慢性丙型肝炎病毒感染灵长类动物中 microRNA-122 的治疗性沉默。
Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.
机构信息
Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
出版信息
Science. 2010 Jan 8;327(5962):198-201. doi: 10.1126/science.1178178. Epub 2009 Dec 3.
Abstract
The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.
摘要
肝表达的 microRNA-122（miR-122）对于培养的肝细胞中丙型肝炎病毒（HCV）RNA 的积累至关重要，但作为抗病毒干预的靶点尚未得到评估。我们发现，用与 miR-122 互补的锁核酸（LNA）修饰的寡核苷酸（SPC3649）治疗慢性感染的黑猩猩，可导致 HCV 病毒血症的长期抑制，而在治疗动物中没有发现病毒耐药性或副作用的证据。此外，对肝活检组织的转录组和组织学分析表明，miR-122 种子部位的靶 mRNA 去抑制、干扰素调节基因下调，以及改善 HCV 诱导的肝病理。SPC3649 治疗的持久病毒学反应而没有 HCV 反弹，有望成为一种具有高耐药屏障的新抗病毒治疗方法。
相似文献
1
Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.
Science. 2010 Jan 8;327(5962):198-201. doi: 10.1126/science.1178178. Epub 2009 Dec 3.
2
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. doi: 10.1128/AAC.04220-14. Epub 2014 Nov 10.
3
Hepatitis C virus therapy: blocking the little microRNA helper of the virus.
J Formos Med Assoc. 2010 Mar;109(3):173-6. doi: 10.1016/s0929-6646(10)60039-3.
4
HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.
Gastroenterology. 2012 Apr;142(4):978-88. doi: 10.1053/j.gastro.2011.12.055. Epub 2012 Jan 13.
5
Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C.
Gastroenterology. 2007 Feb;132(2):733-44. doi: 10.1053/j.gastro.2006.11.045. Epub 2006 Nov 29.
6
Lack of response to exogenous interferon-alpha in the liver of chimpanzees chronically infected with hepatitis C virus.
Hepatology. 2007 Oct;46(4):999-1008. doi: 10.1002/hep.21776.
7
Treatment of HCV infection by targeting microRNA.
N Engl J Med. 2013 May 2;368(18):1685-94. doi: 10.1056/NEJMoa1209026. Epub 2013 Mar 27.
8
Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients.
Antiviral Res. 2014 Nov;111:53-9. doi: 10.1016/j.antiviral.2014.08.015. Epub 2014 Sep 8.
9
Antisense gets a grip on miR-122 in chimpanzees.
Sci Transl Med. 2010 Jan 6;2(13):13ps1. doi: 10.1126/scitranslmed.3000605.
10
IFI35, mir-99a and HCV genotype to predict sustained virological response to pegylated-interferon plus ribavirin in chronic hepatitis C.
PLoS One. 2015 Apr 6;10(4):e0121395. doi: 10.1371/journal.pone.0121395. eCollection 2015.
引用本文的文献
1
MicroRNAs in Liver Cirrhosis: Diagnostic and Therapeutic Perspectives-A Comprehensive Review.
J Pers Med. 2025 Aug 14;15(8):376. doi: 10.3390/jpm15080376.
2
Low levels of tumor suppressor miR-3619 in plasma contribute to malignant outcomes and a target for nucleic acid therapy in esophageal cancer.
Sci Rep. 2025 Jul 27;15(1):27358. doi: 10.1038/s41598-025-12246-6.
3
Cellular miRNAs and viruses: trends in miRNA sequestering and target de-repression.
J Virol. 2025 Jul 22;99(7):e0091425. doi: 10.1128/jvi.00914-25. Epub 2025 Jun 18.
4
MicroRNA nanoformulation: a promising approach to anti-tumour activity.
Invest New Drugs. 2025 May 14. doi: 10.1007/s10637-025-01534-7.
5
MicroRNA Gets a Mighty Award.
Adv Sci (Weinh). 2025 Feb;12(7):e2414625. doi: 10.1002/advs.202414625. Epub 2025 Jan 21.
6
Viral RNA Interactome: The Ultimate Researcher's Guide to RNA-Protein Interactions.
Viruses. 2024 Oct 30;16(11):1702. doi: 10.3390/v16111702.
7
MicroRNA-122 protects against interferon-α-induced hepatic inflammatory response via the Janus kinase-signal transducer and activator of transcription pathway.
Endocr J. 2025 Jan 6;72(1):53-67. doi: 10.1507/endocrj.EJ24-0317. Epub 2024 Oct 1.
8
Hepatic miR-149-5p upregulation fosters steatosis, inflammation and fibrosis development in mice and in human liver organoids.
JHEP Rep. 2024 Jun 4;6(9):101126. doi: 10.1016/j.jhepr.2024.101126. eCollection 2024 Sep.
9
miRNA-Targeted Vaccines: A Promising Approach for Viral Attenuation and Immunogenicity Enhancement.
Curr Gene Ther. 2024 Jul 31. doi: 10.2174/0115665232305431240726113347.
10
Unraveling the miRNA Puzzle in Atherosclerosis: Revolutionizing Diagnosis, Prognosis, and Therapeutic Approaches.
Curr Atheroscler Rep. 2024 Aug;26(8):395-410. doi: 10.1007/s11883-024-01216-4. Epub 2024 Jun 13.
本文引用的文献
1
Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy.
Nat Med. 2009 Jan;15(1):31-3. doi: 10.1038/nm.1902. Epub 2009 Jan 4.
2
Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome.
Cell Host Microbe. 2008 Jul 17;4(1):77-85. doi: 10.1016/j.chom.2008.05.013.
3
Interferon signaling and treatment outcome in chronic hepatitis C.
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9. doi: 10.1073/pnas.0707882105. Epub 2008 May 8.
4
LNA-mediated microRNA silencing in non-human primates.
Nature. 2008 Apr 17;452(7189):896-9. doi: 10.1038/nature06783. Epub 2008 Mar 26.
5
Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver.
Nucleic Acids Res. 2008 Mar;36(4):1153-62. doi: 10.1093/nar/gkm1113. Epub 2007 Dec 23.
6
Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response.
Hepatology. 2007 Nov;46(5):1548-63. doi: 10.1002/hep.21853.
7
Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Antimicrob Agents Chemother. 2007 Dec;51(12):4290-6. doi: 10.1128/AAC.00723-07. Epub 2007 Oct 1.
8
Lack of response to exogenous interferon-alpha in the liver of chimpanzees chronically infected with hepatitis C virus.
Hepatology. 2007 Oct;46(4):999-1008. doi: 10.1002/hep.21776.
9
IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection.
Hepatology. 2006 Dec;44(6):1617-25. doi: 10.1002/hep.21407.
10
Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection.
J Infect Dis. 2006 Oct 1;194(7):895-903. doi: 10.1086/507307. Epub 2006 Aug 29.
Zotero 插件