A biopharmaceutical company in Denmark has designed a drug that blocks a specific microRNA strand involved in replicating hepatitis C, as well as in regulating cholesterol. The company, Santaris Pharma, is the first in the world to successfully test the technique in monkeys.

Researchers have recently found that microRNA plays a key part in regulating genetic transcription. MicroRNA are tiny segments of RNA, and while they do not produce proteins like RNA and DNA, they have the ability to bind with messenger RNA, the deliverer of the genetic “instructions” that are required for protein synthesis. Scientists have found that when microRNA block certain messenger RNA, they also prevent genetic orders from being carried out. If these orders are meant to protect the body from disease, preventing their delivery via microRNA may result in a host of disorders, including cancer, cardiovascular and neuro-related disorders, and viruses such as hepatitis C.

“MicroRNAs appear very involved in the pathogenesis of serious diseases,” says Keith McCullagh, Santaris Pharma’s CEO. “This technology might be used to inhibit a whole range of microRNA, and it might [lead to] a new class of drugs in the pharmaceutical industry.”

For the past few years, multiple research groups have looked for ways to block specific microRNAs. Researchers have had difficulty developing a compound stable enough to bind with microRNA for a long period of time. McCullagh and his colleagues have cleared this hurdle. Using a chemistry technique called locked nucleic acid (LNA), the researchers can generate a three-dimensional compound that successfully locks onto microRNA, forming a duplex that cannot bind with other molecules, such as messenger RNA.

The team tested the compound on microRNA-122, which is involved in the viral replication of hepatitis C and in regulating cholesterol levels. MicroRNA-122 is present in large quantities in the liver, an organ that, McCullagh’s team found, easily takes up the LNA compound. The group developed an aqueous solution containing the compound, and it ran the drug through a number of tests, first in culture dishes, then in primates.

The researchers first injected the compound into a culture dish with human liver cells infected with hepatitis C, and they found that the drug successfully bound up microRNA-122, reducing viral replication in culture. The team then moved on to animal studies and injected the drug three times intravenously, at varying doses, in African green monkeys. The group with the highest dose experienced a 30 to 40 percent drop in cholesterol levels, which lasted about three months. The scientists performed liver biopsies before and after treatment, and they found that the LNA compound effectively bound up microRNA-122 in the liver.

While the drug was able to lower cholesterol levels overall, it did not discriminate between good (HDL) and bad (LDL) cholesterol. McCullagh says that targeting microRNA in order to lower cholesterol may not be the best approach, since there are a number of drugs already on the market that specifically reduce bad cholesterol. However, the study’s main objective was not to develop a cholesterol-lowering drug, but to test the drug’s safety and stability in primates. In these regards, McCullagh says, the drug effectively passed the test.

“From this study, we know once you block 122, the duplex is stable, and 122 stays blocked until it’s metabolized by the cell and removed,” says McCullagh. “The liver also seems to be slow in making more 122, so for both those reasons, we know the effect is relatively long lived.”

Such an effect may be key to combating other diseases related to microRNA, such as hepatitis C. McCullagh’s team has already found that blocking microRNA-122 in culture reduces replication of the virus in human cells.

“It’s interesting that after three doses for five days [in monkeys], we’re getting a long-lasting effect,” says McCullagh. “You might have to give such a drug once a month, but no more than once a week, so you might have weekly treatment for hepatitis C.”

Santaris Pharma plans to start human trials of the drug in the next few months, and it eventually hopes to test the drug on patients with hepatitis C and other related disorders.

Tyler Jacks, director of the Center for Cancer Research at MIT, studies the role of microRNAs in cancers and other disorders. He says that while the Santaris Pharma drug may be effective in treating conditions in the liver, it may not have the same effect on other organs that do not take up the drug as easily.

“For many disease applications, it will be necessary to get efficient delivery to other tissues and organs,” says Jacks. “Still, the data are impressive, and I would be very encouraged about future prospects.”