Small Rna, Big Potential For Treating Hcv

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he estimated 170 million people infected with Hepatitis C virus (HCV) have been living with limited medical options. There is no cure for HCV, and today’s therapies work in only about 40% of the patients. However, recent findings in Stanford’s Department of Microbiology and Immunology have opened the door to discovering a possible new way to treat HCV.

Hepatitis C Virus HCV is one of several different hepatitis viruses that cause inflammation of the liver. Other common hepatitis viruses include food and water-borne Hepatitis A, which does not typically cause a chronic infection, and blood-borne Hepatitis B, which causes chronic disease in 10% of those infected. Vaccines are available for both Hepatitis A and B. Hepatitis C is considered a much more serious virus. At least 80% of patients with acute HCV ultimately develop chronic liver infection, 20% to 30% develop cirrhosis, and between 1% and 5% develop liver cancer. It is the number one cause for liver transplantation in the U.S. Because the virus mutates rapidly, there is no vaccine for HCV. Currently, interferon and ribavirin are the only two drugs prescribed to combat HCV infection, but they are highly toxic and not very effective. The need for a safe and efficacious treatment has led Professor Peter Sarnow and his lab to study how small RNA molecules called microRNAs found in the liver are essential for the replication of HCV. MicroRNAs – Tiny Non-coding Pieces of Genetic Material RNA is a genetic polymer that consists of a sugar backbone and 4 bases: cytosine, guanine, adenine, and uracil. RNA is a critical molecule in biology: in the most general pathway from gene to protein, DNA is first transcribed into messenger RNA (mRNA) before being translated by cellular machinery into a protein product. While mRNA is well known for its critical role in protein synthesis, there are RNA molecules that do not code for any proteins. MicroRNAs are a tiny example of these noncoding pieces of genetic material. Nicknamed “the dark matter of the cell”, these short little strands of RNA are ubiquitous throughout the body’s cells. Scientists believe that these mysterious microRNAs may provide important roles in regulating the activities in a cell. Research into microRNAs has been growing rapidly in the past few years, and in 2005, Wired magazine reported that the number of articles published on the topic of microRNA jumped from just 4 in 2001 to nearly 200 in 2004.

A Connection Between HCV and microRNA While many microRNAs are found throughout the different cells of the body, some are found only in specific cell types.

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miR-122 is a 22 nucleotide microRNA that is found specifically in liver cells. The high abundance of miR-122 in the liver – possibly as high as 65,000 copies - led Sarnow to postulate that there may be a connection between this microRNA and HCV. A postdoc in Sarnow’s lab, Catherine Jopling, added a complimentary strand of nucleotides to liver cells that bound to and sequestered miR-122 so that it could not interact with the HCV genome. This resulted in an 80% decrease in the levels of HCV replication and protein. By looking at the nucleotides in miR-122 and the HCV genome, Sarnow’s team found two predicted sites where miR122 could bind to the HCV genome: one in the 5’ non-coding region and one in the 3’ non-coding region. Further research indicated that the interaction between HCV and miR-122 occurs in the 5’ noncoding region of the HCV genome. Because the inactivation of miR-122 results in reduced levels of HCV, it is possible that antiviral An electron micrograph intervention can be developed based on highlighting the hepatitis C virus. sequestering this microRNA. In fact, Sarnow describes studies, reported by researchers at Rockefeller University and ISIS Pharmaceuticals, performed in mice in which miR-122 was successfully sequestered for up to 3 weeks after injection with a complimentary nucleotide strand without impairing function of the mouse liver. While Sarnow stresses that results from a mouse do not necessarily translate into human treatment, miR-122 sequestration in this way shows a therapeutic potential for an antiviral target that does not directly attack the virus. This is important because HCV would eventually develop resistance to an antiviral drug that directly targets the virus, but it would not be so easy for the virus to develop resistance to an antiviral drug that targets a cellular component. Sarnow’s findings were the first to link a specific microRNA with a major infectious disease, and were published in Science last year. Stanford has entered into a licensing agreement with Alnylam Pharmaceuticals and Isis Pharmaceuticals to explore the possibility of targeting miR-122 to combat HCV. Research continues into the role of miR-122 in HCV replication. Studies have shown that while the miR-122 sequestered mice appear healthy, 300 genes were upregulated and 300 were downregulated. “The big question is,” Sarnow asks, “what is the normal function of the microRNA?” Further research will hopefully elucidate this question and help develop an antiviral treatment for HCV patients. S Sean maThewSon is a junior majoring in Chemical Engineering. When not in class or lab, he can sometimes be seen swinging away on the Stanford driving range.

volume iv 19

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by Sean Mathewson

biology + medicine