RxGen Inc.

Monkey business.
By blocking tiny pieces of RNA called microRNA in African green monkeys, researchers have shown the potential of using the strategy for fighting disease in humans.

MicroRNA Sets Stage for Human Therapies

Scientists have taken a big step toward developing therapies based on naturally occurring tiny RNA molecules called microRNAs. In the first successful experiment with primates, researchers have blocked microRNAs to lower cholesterol levels in monkeys. This achievement builds hope that the strategy could one day be used to attack human diseases. Safety concerns still linger, however.

MicroRNAs regulate gene expression and play key roles in many biological processes, such as cell death and metabolism. Scientists have eyed microRNAs as potential targets for disease-fighting treatments because their malfunction has been implicated in cancer, heart disease, viral infections, and other disorders. Ailing mice have recovered thanks to microRNA-based therapies, but researchers have worried whether blocking overactive microRNAs in people will be feasible and safe. The new tests were led by Santaris Pharma, a biotech company in Horsholm, Denmark, focused on developing microRNA-based therapies. The company, which has developed a way to block microRNAs that is different from the strategies previously used in mice, put their method to the test by targeting a microRNA called miR-122 that regulates cholesterol levels.

Sakari Kauppinen, a molecular geneticist at Santaris, teamed with collaborators from Stanford University and RxGen, a biotech company in Hamden, Connecticut. They generated a short sequence of DNA that would bind to and block the function of miR-122. The DNA sequence was combined with a piece of RNA designed to increase its binding power to the microRNA. The researchers then injected the modified DNA sequence into African green monkeys at varying doses. In the five healthy monkeys that received the highest dose, cholesterol levels dropped by a maximum of 40% within 23 days, a strong indication that the therapy had stymied miR-122. Five animals that received a lower dose had a cholesterol drop of 20%. Of the 15 animals injected with the microRNA blocker, none showed any signs that the treatment was toxic, the researchers report online today in Nature. Kauppinen says his company's goal is to develop a hepatitis C treatment based on miR-122, because this microRNA is involved in replication of the virus in people.

John Rossi, a molecular geneticist at the City of Hope in Duarte, California, says the findings open the door for using microRNA-based therapies in people. That's because the research shows it is possible to get these microRNA blockers into the cells where they are needed, without causing apparent harm to the animal. This approach could now be adopted for developing treatments for other conditions, by generating DNA sequences that target specific microRNAs involved in diseases, he says.

Although no serious side effects were detected in the monkeys, both Rossi and Peter Kang, a neurologist at Children's Hospital Boston, say the safety of blocking microRNAs in humans must be carefully studied. Many microRNAs regulate numerous genes, so knocking down the expression of just one could have untold effects on the body, Rossi says.

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