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by Sean Mathewson
T
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 non-
coding 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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http://www.genome.gov/Pages/News/Photos/Other/DNAKit_illustration_image.jpg
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.
http://intramural.niddk.nih.gov/images/hellert-1.jpg
By looking at the nucleotides in miR-122 and the HCV
genome, Sarnow’s team found two predicted sites where miR-
122 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