Mechanism may help fight hepatitis C
BY MITZI BAKER
Last year Peter Sarnow, PhD, professor of microbiology and immunology at the School of Medicine, identified a previously unknown mechanism that the hepatitis C virus uses to replicate, yielding a promising new approach to combating the disease-causing virus. On April 5 at the Experimental Biology meeting in San Francisco, Sarnow discussed recent developments in this work—including his partnership with two pharmaceutical companies that seeks to use the new understanding of the virus to develop treatments.
According to the World Health Organization, hepatitis C virus infects 170 million people worldwide. About 70 percent of those infected develop liver disease, including cirrhosis and liver cancer. In the United States, it is the most common blood-borne viral infection, killing more than 10,000 people each year. Currently available treatments are expensive and do not work in about half of the cases.
"Normally with an RNA virus like hepatitis C, resistance to antivirals very quickly emerges, so the drug is not effective any more," Sarnow said in an interview before his presentation. Sarnow has studied the virus for years, sorting out how the viral RNA amplifies in cultured liver cells.
In the normal sequence of events, genetic information is stored in DNA and then is copied into RNA, which serves as a template to create proteins. With RNA viruses such as hepatitis C, the genetic information is stored in RNA instead of DNA.
RNA is genetically more unstable than DNA, resulting in the accumulation of many mutations. These mutations allow the virus to outwit the immune system and develop resistance to antiviral medication.
Sarnow's group has shown that a small fragment of RNA found in the liver, known as a microRNA, is necessary for hepatitis C to grow and reproduce. This work, published in September 2005 in the journal Science, was the first to link the presence of a specific microRNA with a major infectious disease.
When the researchers inactivated the microRNA, called miR-122, the amount of hepatitis C virus RNA was reduced by approximately 80 percent. "The cool thing is that here, an antiviral is encoded by a host function and not by the virus, so it cannot change," said Sarnow. In other words, because the virus needs miR-122 to replicate, there is no way the virus could develop resistance to a strategy that inactivates miR-122.
A couple of years ago, Sarnow learned that other scientists had discovered miR-122, found only in the liver. He knew that there could be up to 65,000 copies of miR-122 per cell in the liver. "And we know that the virus can persist in the liver for as long as 30 years, so we made the hypothesis that the virus might interact with miR-122 in some way," he said. "It turns out that yes, the virus grabs it for its own good."
"This is a completely different way for microRNA to interact with its target from what is known and it brings up the idea that other microRNAs might work like that," said Catherine Jopling, PhD, a postdoctoral researcher in Sarnow's laboratory who spearheaded the work. "But nobody's been looking for that."
The researchers think that their findings may have therapeutic potential for a new antiviral target that does not attack the virus directly.
"If you can lower the amount of the microRNA in the liver without affecting liver function maybe this will help lower the viral load," said Sarnow. Stanford has entered into a licensing agreement with Alnylam Pharmaceuticals and Isis Pharmaceuticals to explore the possibility of using miR-122 as a novel therapeutic against hepatitis C.
The big question is what this microRNA normally does in the liver. It is possible that lowering microRNA levels in the liver might produce an undesirable outcome, such as cancer, said Sarnow. However, recent promising reports from researchers at Rockefeller University, Alnylam and Isis have demonstrated that miR-122 can be inactivated in mouse liver for some time without impairing liver function.
The Experimental Biology meeting is an annual gathering of groups covering a range of scientific disciplines, including anatomy, biochemistry, molecular biology, pharmacology and pathology. This year an estimated 12,000 scientists attended the event at the Moscone Center in San Francisco.