Nearly 3% of the world’s population – about 175,000,000 individuals – are infected with hepatitis C virus (HCV), and 3-4 million new infections are added each year. A high percentage of these become life long, chronic infections, which may lead to cirrhosis, hepatocellular carcinoma, and death. No vaccine is available, and the only antiviral treatment, pegylated interferon plus ribavirin, is often ineffective and has adverse side effects. The extent and severity of hepatitis C has stimulated the development of many new antiviral compounds, including protease and polymerase inhibitors. Perhaps one of the most unusual treatments being considered is one that directly targets a small RNA, known as a microRNA (miRNA), that is abundant in the liver.
Micro RNAs are single-stranded RNA molecules 21-23 nucleotides long which regulate the expression of about 30% of all mammalian protein-coding genes. They act by binding to the 3′-non coding region of mRNAs which leads to degradation of the mRNA or inhibition of translation. When miRNAs were first discovered, many virologists searched for target sequences in viral genomes to discover new ways to inhibit viral replication. A binding site for a liver-specific miRNA, called miR-122, was found in the RNA genome of HCV. However the target site for miR-122 was found in the 5′-noncoding region of the mRNA, not in the 3′-end. To the investigators’ surprise, binding of miR-122 to the HCV RNA stimulated viral replication. HCV replication in cells lacking miR-122 is significantly reduced compared with cells that produce miR-122.
The requirement of miR-122 for HCV replication suggested that this miRNA could be a target for therapeutic intervention. One approach has been the use of antagomirs, which are small synthetic RNAs that are complementary to the miRNA target. By binding to the miRNA, antagomirs block their ability to bind the target sequence and inhibit their function. An antagomir to miR-122 was found to impair HCV replication in cultured liver cells. Last year, a phase I clinical trial of an miR-122 antagomir was initiated in humans.
An important question is whether inhibition of miR-122 influences the expression of cellular genes which might lead to adverse side effects. If the antagomir is ever licensed, it will have another benefit besides inhibiting HCV replication: reduced cholesterol levels. miR-122 is believed to be involved in the regulation of cholesterol, fatty acid, and lipid metabolism, and African green monkeys who were administered the miR-122 antagomir had reduced plasma cholesterol.
C. L. Jopling, MinKyung Yi, Alissa M. Lancaster, Stanley M. Lemon, Peter Sarnow (2005). Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA Science, 309 (5740), 1577-1581 DOI: 10.1126/science.1113329
Jan Krützfeldt, Nikolaus Rajewsky, Ravi Braich, Kallanthottathil G. Rajeev, Thomas Tuschl, Muthiah Manoharan, Markus Stoffel (2005). Silencing of microRNAs in vivo with ‘antagomirs’ Nature, 438 (7068), 685-689 DOI: 10.1038/nature04303
Y SHAN, J ZHENG, R LAMBRECHT, H BONKOVSKY (2007). Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes Gastroenterology, 133 (4), 1166-1174 DOI: 10.1053/j.gastro.2007.08.002
Joacim Elmen, Morten Lindow, Sylvia Schütz, Matthew Lawrence, Andreas Petri, Susanna Obad, Marie Lindholm, Maj Hedtjärn, Henrik Frydenlund Hansen, Urs Berger, Steven Gullans, Phil Kearney, Peter Sarnow, Ellen Marie Straarup, Sakari Kauppinen (2008). LNA-mediated microRNA silencing in non-human primates Nature, 452 (7189), 896-899 DOI: 10.1038/nature06783
Hi there, interesting blog!
So, what's the chemical structure of miR-122 and its antagomir?
miR-122 sequence/structure is here: http://bit.ly/BmBxY. The antagomir is the complementary sequence, modified chemically for stability. See this article for more details: http://bit.ly/gH7aJ.
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Nice article.. Here in the Philippines, About 3% of our population are suffering from hepatitis.. Hope our government will do something about this.. By the way.. Thanks for posting this..
I have been suffering of back and joints pain and muscular tension. I have been that my doctor prescribed and I feel a lot better now. But I was thinking about some natural remedies because I don't enjoy taking pills. Anodyne therapy seems to be exactly what I needed. There can't be anything harmful about light and the results sound promising.
im wondering when a new med will come out for hep c.i tride interferon and it did not work.can you tell me when this new drug will come out to save my life. rick
when will a new drug be readdy for people that took interferon and did not work for them.
im wondering when a new med will come out for hep c.i tride interferon and it did not work.can you tell me when this new drug will come out to save my life. rick
when will a new drug be readdy for people that took interferon and did not work for them.
Treatment of hepatitis C shortly after a person living with HIV are infected, it has the best chance of success.Approximately two thirds of people living with HIV who have hepatitis C to obtain a therapeutic response is sustainable, but rather a response to treatment is only seen in about one third of HIV-positive patients with hepatitis Chronic C.
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I think this is great news.If there is a new drug which can fight against hepatitis c and win I guess this should be launched immedialtely on large scale so everybody who suffers of this disease can treate him self.It is wonderful to know that there are people dedicating their life to a cause like this but I guess we need to protect ourselves too.We can;t expect sombody else to take care of us, of our health.
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I really hope they’re able to get these new medicines into the market quickly to help as many as possible.Â
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