BioEd Online

Cholesterol levels have been lowered in mice by using tiny pieces of genetic material to block a particular gene. The demonstration shows that the experimental technique, called RNA interference (or RNAi), could be a practical way of curing a wide range of diseases.

RNAi works by using small molecules of RNA to trigger a cell to shut off a particular gene, for example, one that codes for a harmful protein. Clinical trials that use RNAi to treat an eye disease called macular degeneration have already begun.

But scientists have had a hard time finding a convenient way to deliver the treatment to patients so that it reaches the right part of the body. In the macular degeneration trials, for example, scientists inject the treatment directly into the eye.

Researchers from the biotechnology company Alnylam, based in Kulmbach, Germany, and Cambridge, Massachusetts, have figured out a way to solve the problem, at least for treating high cholesterol. They modified the RNA molecule used to trigger the interference by attaching a cholesterol molecule to it.

Cells that make cholesterol have cholesterol receptors on their surface, so that they can sense levels of the molecule in the blood. Adding the cholesterol molecule to the RNA ensures that the complex is taken up specifically by these cells, in the liver and small intestine.

When the researchers injected this modified molecule into mice, they found that it cut the animals' levels of 'bad' cholesterol by 44%. They report their results in this week’s Nature¹.

Simple solution

Another concern about RNAi has been whether the therapy might affect genes other than the ones targeted, causing side-effects. The researchers checked the activity of a few genes unrelated to their target gene, and found that they were not affected.

The company is excited about the result. "We view our work as a historic step forward in the development of RNAi therapeutics as a potential new class of drugs," says John Maraganore, head of Alnylam.

He says the company aims to develop similar methods to treat other sorts of diseases, such as diabetes, obesity and cancer. "There are clearly many diseases of interest here," he says.

Other researchers agree that the new method has removed a major roadblock that could have prevented RNAi from moving to the clinic.

"This is a fairly simple solution to a problem that could have been immense in this field," says John Rossi, a molecular biologist at the Beckman Research Institute of the City of Hope in Duarte, California.

But he points out that Alnylam still needs to overcome many practical issues before its research in mice can be translated into patients. The doses used in the mice were quite high, and would be costly and impractical to give to people. And it's not clear how often a person would need to be injected with the treatment, or whether it could be delivered in some other form.

Alnylam says it is working on these issues, and hopes to design more effective molecules that could be used in smaller doses in the future. In the meantime, it will file a clinical trial plan with the Food and Drug Administration next year, which will use RNAi to treat an eye disease. If its plan is approved, Alnylam will be the third company so far to ask the federal agency to approve an RNAi therapy.