TARGETING MICRO-RNA KNOCKS OUT HEPATITIS C

TARGETING MICRO-RNA KNOCKS OUT HEPATITIS C
Blocking a small molecule, a new drug reduces levels of the virus, chimp study shows
Science News Jan 2 2010

If the Bible’s David were a modern doctor, he might appreciate a new strategy aimed at stopping a Goliath health threat: Bringing down the hepatitis C virus with the help of tiny, precisely targeted molecules.

The possible new treatment for hepatitis C infections shows promising results in chimpanzees, researchers report online December 3 in Science.

A compound called SPC3649 sequesters a small genetic molecule known as microRNA-122, keeping it away from the virus. The treatment reduced levels of hepatitis C virus in infected chimps, apparently without serious side effects, say scientists from the Danish drug company Santaris Pharma and colleagues at the Southwest Foundation for Biomedical Research in San Antonio. The virus also did not develop resistance to the drug during the study.

The World Health Organization estimates that 3 percent of the world’s population is infected with hepatitis C. About 170 million people worldwide carry the virus chronically, putting them at risk for liver cirrhosis or liver cancer.

“It’s really a breakthrough, not only for hepatitis C research, but also in gene therapy,” says Peter Sarnow, a molecular virologist at Stanford University. The research is still in very early stages and results in people may not match those from tests in chimpanzees, cautions Sarnow, who was not involved with the current study.

Previously, Sarnow and other researchers had discovered that hepatitis C viruses hijack the miR-122 molecule, a snippet of RNA made in large amounts in the liver. The microRNA is known to regulate about 300 genes, including many involved in making cholesterol. All classes of hepatitis viruses contain a string of RNA letters that complement the letters composing miR-122, which allows the two to bind. The virus needs the microRNA in order to replicate within liver cells, although the details of the interaction aren’t clear.

“We really don’t know why the virus is grabbing this microRNA,” Sarnow says. But blocking the virus-microRNA interaction proves catastrophic for the virus, Sarnow’s group showed in previous experiments in laboratory dishes.

In the new study, researchers used a small compound called a locked nucleic acid to inhibit the interaction between miR-122 and the virus. The compound, SPC3649, is also a small piece of RNA that attaches to miR-122. The compound’s backbone has been chemically altered to lock it into a stiff structure, which is long-lived and extremely efficient at latching on to miR-122 to pull it away from the virus, says Henrik Ørum, the chief science officer for Santaris Pharma in Denmark and a coauthor of the study.

Once a week for 12 weeks, researchers injected the compound into chimpanzees harboring chronic hepatitis C infections. Two chimps were given a low dosage of the compound — 1 microgram of the compound per kilogram of body weight. Two other chimps got a higher dose — 5 micrograms per kilogram of body weight. Over the 12 weeks of treatment, virus levels in the chimps given the higher dose “dropped and dropped,” says Ørum. One of the chimps given the lower dose also showed a decline in virus levels during the study, but the other low-dose animal did not. And the low viral counts lasted for months after treatment stopped. Virus levels slowly climbed again beginning about five months after treatment stopped, Ørum says.

The most exciting finding of the study is that the hepatitis C virus did not develop resistance to the treatment, Sarnow says. Most other antiviral drugs target proteins that a virus makes to infect or survive in the host’s cells. In trials of these drugs, it’s common for a virus to quickly develop resistance, mutating genetically and shaking off the drug’s effect. The new treatment is different because, instead of targeting the virus, it targets a microRNA made by the host, in this case the chimpanzee.

At least 800 other microRNAs are made in the liver, and Sarnow says he expected hepatitis C to be able to mutate to substitute one of the other 800 for miR-122. That did not happen during the study, indicating that the drug could be a good choice for long-term therapies.

Cholesterol levels also dropped in chimpanzees given the high dose of the drug, the study showed. This side effect was expected because miR-122 regulates cholesterol genes. Researchers had been concerned that the side effect might become problematic if levels of both low density lipoprotein (“bad” cholesterol) and high density lipoprotein (“good” cholesterol) dropped too far. In previous tests with African green monkeys, both types of cholesterol were reduced, but in the new study, good cholesterol levels didn’t dip as much as those of bad cholesterol.

The SPC3649 compound is currently undergoing clinical trials to test its safety in healthy human volunteers, Ørum says. The long-term effects of taking the compound are not known, and Sarnow cautions that several of the genes regulated by miR-122 are involved in cancer.

“There’s a lot more work to be done, but this is definitely encouraging,” says Catherine Jopling, a molecular biologist at the University of Nottingham in England. “It’s a start on what might turn out to be a very effective avenue for new therapies.”