Treatment of HCV Infection by Targeting MicroRNA — NEJM
Treatment of HCV Infection by Targeting MicroRNA — NEJM
In our Chemistry of Cancer class recently, we have been discussing the roles of microRNAs (miRNA) in carcinogenesis. In the March 27, 2013, edition of New England Journal of Medicine (link above), researchers have performed initial clinical trials of a potentially therapeutic drug that targets a specific miRNA that the hepatitis C virus (HCV) uses for replication. This miRNA (miRNA-122), although naturally produced in the liver, binds to a highly conserved untranslated region of the HCV genome and increases the stability and propagation of the HCV RNA. Usually, miRNAs are important for post-transcriptional modification and regulation of RNAs.
This drug, Miravirsen, binds to the miRNA-122. What makes this a novel therapeutic is that it targets a site in the host cell's "machinery" rather than in the HCV genome or proteome. Potentially, this could help prevent the HCV from being able to mutate to evade the action of this drug and become resistant. Some of the patients on this study had their levels of HCV RNA drop so low that they were no longer measurable even weeks after the study had ended.The long-term side effects of this drug are unknown at this time; obviously, additional studies are warranted. However, these results are promising, and perhaps something like this could also have potential chemotherapeutic applications in the future.
For a more "everyday" read on the importance of this research, check out the Science News article at the link below:
Hepatitis C drug goes after patients’ RNA
In our Chemistry of Cancer class recently, we have been discussing the roles of microRNAs (miRNA) in carcinogenesis. In the March 27, 2013, edition of New England Journal of Medicine (link above), researchers have performed initial clinical trials of a potentially therapeutic drug that targets a specific miRNA that the hepatitis C virus (HCV) uses for replication. This miRNA (miRNA-122), although naturally produced in the liver, binds to a highly conserved untranslated region of the HCV genome and increases the stability and propagation of the HCV RNA. Usually, miRNAs are important for post-transcriptional modification and regulation of RNAs.
This drug, Miravirsen, binds to the miRNA-122. What makes this a novel therapeutic is that it targets a site in the host cell's "machinery" rather than in the HCV genome or proteome. Potentially, this could help prevent the HCV from being able to mutate to evade the action of this drug and become resistant. Some of the patients on this study had their levels of HCV RNA drop so low that they were no longer measurable even weeks after the study had ended.The long-term side effects of this drug are unknown at this time; obviously, additional studies are warranted. However, these results are promising, and perhaps something like this could also have potential chemotherapeutic applications in the future.
For a more "everyday" read on the importance of this research, check out the Science News article at the link below:
Hepatitis C drug goes after patients’ RNA
Wow, this emerging treatment for HPV infection looks extremely promising! Instead of targeting HCV directly, this new drug (miravirsen) clamps on to mRNA-122, which HCV uses for its replication. So far, clinical studies involving test groups have yielded exciting results. In several studies, a definite trend emerged: Patients who received the highest dosage of miravirsen experienced the most drastic reduction in virus levels, while those without the drug showed no discernible differences. Quite often in medicine, treatments are found in using the right combination of drugs, a sort of drug “cocktail” that produces the right chemical effect. Certainly, potentially damaging side effects (such as interference with cholesterol synthesis) should be considered before this drug is widely used. The possible side effects, however, seem preferable to living with active HPV.
ReplyDeleteThis new treatment turns the traditional therapeutic model on its head: Rather than targeting the invader itself, this therapy makes changes to the host organism so the invader cannot gain a firm foothold. Even within the next five to ten years, this paradigm shift in how disease is treated can offer cures for other viral diseases like AIDS as well as certain cancers. By employing an miRNA-specific drug used in tandem with the appropriate virus-interfering factor (eg., interferon) one could possibly prevent T-lymphocyte infection by HIV. These therapies can also target abnormal cell-growth pathways that are characteristic of cancerous diseases. MiRNA-targeted therapies offer a storehouse of potential cures that scientists have only begun to explore.
This truly is a novel approach to treatment. I expect that this approach could be valuable against many diseases. By modifying our cells to be "uninviting" to the virus, we bypass the need to modify the virus itself. Unlike a vaccine, we are not preparing antibodies against the virus. Instead, the virus is being "starved" out since it cannot make the necessary attachments to reproduce and tap into the host cells' resources. Currently, certain genotypes of Hepatitis C are more treatable than others, but assuming the region to which mRNA-122 binds is identical across the genotypes, miravirsen could level the playing field. I look forward to seeing what further studies on miravirsen conclude, and what other advances could be made using this method of treatment.
ReplyDeleteRNA is becoming an increasing popular target for treating disease. RNA is responsible for several activities of the cell. Viruses utilize host cells’ cellular machinery to replicate themselves. This is what makes RNAs that control viral gene expression prime targets for disease control. If certain genes cannot be expressed, viruses may be essentially neutralized. This is exactly what the researchers found with the hepatitis C virus (HCV). Patients who received large doses of miravirsen had significantly decreased levels of HCV. Miravirsen targets a specific miRNA that adds stability to HCV viral mRNA. This increased stability allows HCV to spread very efficiently. The HCV may have only been weakened or unable to spread due to the effects of miravirsen. That is why some patients were treated with interferon in addition to miravirsen. Interferon is a different treatment for HCV. Miravirsen and interferon both combat the HCV in different ways. Four patients who received both treatments had significantly lower levels of HCV even 14 weeks after the last treatment. This small clinical study had pretty astounding results. HCV is an extremely difficult virus to completely eliminate. Many patients will have HCV until the day they die. Usual treatments have only been successful in preventing the worst symptoms of HCV, such as liver damage. However, miravirsen is a treatment that is capable of completely eliminating HCV with the aid of typical HCV treatments. There is another benefit of RNA treatments. RNA treatments can bypass the virus itself and treat the problem in the host cells. By blocking the HCV’s ability to effectively use the host’s cellular machinery, the HCV cannot replicate and spread efficiently. Additionally, the HCV cannot easily adapt or become resistant to this treatment because the treatment does not directly attack the virus. Overall, RNA treatment is a promising and exciting form of treatment for viruses. The fact that RNA treatment can help neutralize HCV, a virus proven to be extremely resilient to treatment, makes this type of treatment all the more exciting.
ReplyDeleteIt is interesting to me that the microRNA itself binds to 5’ untranslated region of the virus, which increases the translation of the virus and causes it to propagate rapidly. The most interesting part to me is that these specific microRNA’s (miR122) usually bind to the 3’ UTR and repress translation of the mRNA. Along with several other proteins; however, the microRNA stabilizes the viral RNA machinery. The advantage that scientists have is that the 5’UTR binding site for the microRNA on HCV RNA is a consensus sequence. In other words, it is nearly identical in all strains of the Hepatitis C virus. This is beneficial because it means that a drug that targets this specific region has hopes to work on most strains of the virus, which will decrease HCV RNA replication and eventually halt the virus in most patients. This is what the drug Miravirsen does. Upon prolonged use of the drug, many patients showed massive deductions in HCV RNA production. Although this is promising, there could be undiscovered consequences. The effects of the drug on other cells in the body are unknown, but further tests will verify either success or doubt.
ReplyDeleteNote: There are additional binding sites for miRNA on HCV RNA in both the 5’UTR and 3’UTR; however, both binding sites increase RNA production in the virus. All of the known sequences are also very similar and most of them are conserved among genotypes of HCV.
Additional resources:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586803/
http://omim.org/entry/609532?search=HCV&highlight=hcv
http://www.ncbi.nlm.nih.gov/books/NBK1624/
I knew someone who had Hepatitis C (Hep-c), but he was also an alcoholic, so I’m pretty sure his liver was double cirrhosis-ed. I had no idea how common Hep-C was and that if a person was born during 1945-1965 (baby boomer) they are five times more likely to be infected. 75% of adults with hepatitis C were baby boomers [1]. It is the most common type of viral hepatitis in the US spread through contact with blood from an infected person. More than 15,000 Americans die each year from hepatitis C-related illness [1].
ReplyDeleteSo for there to be a drug that actually works, it would greatly help many people. This new compound the researchers found offers an approach that sets it apart from all the previous forms of treatment: it interferes with the RNA of the virus (kicking him where it really hurts).
In the clinical trials, most of a small group of patients who took the experimental drug, experienced the virus levels decrease even to the point past detection. The drug targets genetic material in the liver named microRNA-122. The normal pathway for the hepatitis virus is to attach to this RNA, so that it can increase the stability it needs to replicate while hiding from immune system.
1. http://www.sciencedaily.com/releases/2013/04/130426211102.htm