It is only a few years since tiny RNA molecules called microRNAs were found to have roles in disease, but a therapeutic approach that targets one of them is already yielding promising results. Sakari Kauppinen and his colleagues at Santaris Pharma in Hørsholm, Denmark, in collaboration with the Connecticut-based company RxGen and Stanford University in California, have successfully blocked the activity of one type of microRNA in non-human primates. And the compound they developed has potential as a treatment for hepatitis C.

MicroRNAs regulate protein synthesis by binding to the messenger RNAs that provide the 'recipe' for protein construction, repressing the relevant protein's production. The mechanism is important in many biological processes, and has also been implicated in a number of disorders, including cancer and cardiovascular disease.

In 2005, Kauppinen —then at the University of Copenhagen — collaborated with Ronald Plasterk, who was then at the University of Utrecht in the Netherlands. They used synthetic RNA analogues called locked nucleic acids (LNAs) — which, when incorporated into a DNA molecule, enable it to bind more effectively to a complementary RNA sequence — to specifically detect microRNAs in zebrafish embryos. “LNA turned out to be an excellent tool for microRNA research. That same year, the first cancer-causing microRNAs were described,” Kauppinen recalls.

Excited by these developments, Kauppinen contacted the management team at Santaris Pharma with the idea of developing an LNA-based approach to silence microRNAs. “We immediately connected on this idea,” says Kauppinen, who was offered a position at the company to head the microRNA research team.

In 2006, Kauppinen and his colleagues at Santaris started testing LNA-based compounds aimed at targeting microRNA-122, a microRNA expressed in the liver that had been shown to assist the replication of hepatitis C virus in liver cells. MicroRNA-122 was an attractive target both because of its role in this important disease and because its activity can be easily monitored in animals. Three earlier studies had shown that when microRNA-122 was blocked in mice, the animals exhibited lower blood-cholesterol levels.

By screening several LNA-based compounds, the team found one that produced cholesterol-lowering effects in mice at very low doses. In addition, the compound effectively inhibited replication of hepatitis C virus in a liver-cell assay developed at Stanford.

Encouraged by the results, the team decided to move to a model closer to humans. “We wanted to know whether our compound was effective and our silencing approach safe,” says Kauppinen. He approached colleagues at RxGen who were using African green monkeys to test potential therapies.

When the LNA compound was given to monkeys, the animals showed dose-dependent lowering of cholesterol (see page 896), and the effect was longer lasting than in mice. “It took about three months before cholesterol returned to baseline levels in the group that received the highest LNA dose,” says Kauppinen. “And, encouragingly, the compound did not seem to have any toxic side effects in primates.”

Santaris Pharma is now taking the first steps towards bringing the compound to the clinic as a potential hepatitis C therapy. “We have plans to do a safety study in healthy volunteers later in 2008,” says Kauppinen. “The pace at which the field is moving is incredible.”