An experimental drug developed by Danish startup Santaris effectively controls the hepatitis C virus in chimpanzees without creating drug-resistant forms of the virus--a major advantage over other compounds in clinical development. The compound, a synthetic nucleic acid that binds to a microRNA molecule required for viral reproduction, is now in early-stage clinical trials. It is the first microRNA-targeting drug to be tested in humans.

Approximately 170 million people across the globe are infected with the hepatitis C virus, a chronic infection that can lead to cirrhosis, liver cancer, and the need for a liver transplant. While drugs exist to treat the virus, they carry serious side effects and work in fewer than half of all infected patients. "The treatment is very harsh and needs to be taken for 48 weeks," says Robert Lanford, the lead author on the new study, which was published online today in Science. "Most people can't tolerate it that long, especially if they have liver disease."

Existing drugs suppress the virus by boosting the patient's immune system. The Santaris drug targets the hepatitis C virus more directly by binding to a short piece of RNA called a microRNA, which the virus needs to replicate. The research is part of a larger effort over the last decade to develop methods of selectively targeting and silencing RNA molecules to treat a number of diseases.

DNA and RNA are made of a series of chemical letters. In an approach called "antisense therapy," molecules designed to complement a sequence of these chemical letters in a target piece of RNA or DNA bind to the target, thereby blocking its function.

One of the major challenges in developing RNA- and DNA-based drugs is creating molecules that are stable enough to remain in the bloodstream until they reach the target tissue. One option is to encase the molecules in special molecular packaging, but that approach adds another layer of complexity to drug development. Santaris has developed a novel chemistry that creates stable DNA molecules that can be injected into the blood and remain there long enough to be taken up by the liver, where the virus resides.

To create the molecule, Santaris scientists altered the structure of a subset of bases within a short strand of DNA, using a technology called "locked nucleic-acid chemistry." The alterations make the molecule highly stable and give it a strong affinity to its RNA complement--in this case, a microRNA called miR-122 that is made by the human genome and which the virus needs to replicate.

"Whereas other chemistries invented in the last 20 years as a means to improve the [binding] properties of oligonucleotides [short strands of RNA or DNA] provide one degree of improved binding, locked nucleic acids provide fivefold to tenfold improvement," says Henrik Orum, Santaris's vice president and chief scientific officer. "It's really a quantum leap in affinity."