Science Editor

A study published in the Dec. 3, 2009, issue of Sciencexpress reported that treating chimpanzees with a drug that sequesters miR122 - a microRNA that regulates the expression of liver genes, and which the hepatitis C virus hijacks for its own replication in infected individuals - led to a decrease in viral load of several orders of magnitude that far outlasted the three-month treatment.

Though the treatment did not enable the animals to clear hepatitis infection, senior author Henrik Oerum told BioWorld Today that the compound SPC3649, which is now in Phase I trials, "could become an important new drug" as part of a combination regimen. Hepatitis C infects 170 million people worldwide, is a risk factor for cirrhosis and liver cancer, and only responds to the current standard treatment in about half of patients.

Oerum, vice president and chief scientific officer at Danish company Santaris Pharma A/S, said that SPC3649 "is breaking new ground" as the first drug that targets a host miRNA to battle a viral infection. The advantage of this approach is that it is hard for the virus itself to evolve resistance to the drug, though the target needs to be carefully chosen. "What you need to find is a host factor that is not essential for the host," but is essential for the virus, he said.

MiR122 fits the bill, Oerum added, in that "it is not an on-off switch" for the genes it regulates; "it is a fine-tuner."

But while miR122 is not essential for the host, at least not in the short run - Oerum stressed that "we do not intend [SPC3649] to be a chronic administration" - the hepatitis C virus needs it to replicate. Oerum and his team from Santaris, Danish Aalborg University, and the Southwest National Primate Research Center in San Antonio treated four chimpanzees each with either high or low doses or SPC3649 for 12 weeks. Both animals receiving the high dose and one of the two receiving the low dose showed a decrease in viral load that far outlasted the end of treatment.

MiR122 regulates the expression of a number of genes in the liver; several of those genes are involved in controlling lipid biosynthesis, and so it is not too surprising that the major side effect of SPC3649 was on cholesterol levels.

In fact, the compound lowered cholesterol by about 30-40 percent, which, Oerum said, is "a bit better than most of the statins." (There is no plan, however, to test the compound specifically for that purpose, since it is not specific for "bad" LDL cholesterol but lowers blood lipid values across the board.)

Aside from its effects on cholesterol, Oerum said that despite a broad effort to monitor possible side effects, "we haven't seen anything that is unexpected or cause for concern" after administration of SPC3649. "If anything, the liver pathology improved slightly" for the duration of the treatment.

Oerum acknowledged that "the objective of any HCV treatment today is to eradicate the virus and cure the patient" - a goal that SPC3649 does not achieve, at least not on its own. But Oerum and his team believe that it may be able to do so in combination with another new treatment approach, specifically targeted antiviral treatment for hepatitis C or STAT-C treatments. Stat-C treatments, a group of compounds which target specific viral functions, are initially highly effective, but "directly targeting makes them very sensitive to the significant mutational potential the HCV has." In contrast, when they sequenced hepatitis C taken from the chimpanzees after treatment with SPC3649, Oerum and his team found no evidence that the virus had mutated to be able to get around the miR122 sequestration.

Oerum believes that such combination treatments are the way of the future; he predicted that "viral treatments in the future will have a cocktail approach," as is already the case for HIV.

Another way in which SPC3649 might prove useful is its effect on interferon-induced gene expression. The current standard treatment for hepatitis C consists of pegylated interferon-gamma plus ribavirin. The role of interferon-gamma in the cocktail is to increase the expression of certain antiviral genes. But in some people, so-called "null-responders," interferon has no effect because the genes it is supposed to affect are already expressed at high levels. Chimpanzees also express interferon-induced genes at high levels and as such, Oerum said, are considered models of null-responders.

In their study, Oerum and his colleagues found that administration of SPC3649 normalized the expression levels of interferon-activated genes in the chimps; if the same turns out to be true in humans, it could make null-responders sensitive to the effects of interferon.