More Effective RNA-Based Drugs

A technique for delivering gene-silencing RNA is able to combat prostate cancer in mice.

The ability to shut down specific disease-causing genes could be a powerful weapon against cancer and infections such as HIV. A recently discovered technique, called RNA interference, in which precisely designed, short bits of RNA selectively interfere with cells' ability to make specific proteins, promises to do just that. But while RNA interference has proven to be a powerful tool for studying the genome, and has been translated into some potential drugs, getting RNA inside the right cells in the body has turned out to be difficult -- limiting its therapeutic value.

Researchers at Duke University have now designed a simple way to make these therapeutic RNAs and have used them to successfully combat a form of prostate cancer in mice --without adverse effects in other parts of the body. Using the technique, therapeutic RNAs could be designed for many other kinds of cancer and other diseases, according to Bruce Sullenger, chief of experimental surgery at Duke University Medical Center.

The main obstacles to using RNA interference to combat diseases, says John Rossi, chairman and professor of molecular biology at the Beckman Research Institute in Duarte, California, are ensuring that the RNA is taken up by the targeted cells so that it can do its work and that it is directed only at a tumor or a diseased area. Sullenger's approach could make it possible to administer RNA therapy through the bloodstream.

The RNA therapies that have reached clinical trials are administered by directly applying them to easy-to-reach tissues. For example, Alnylam, a startup based in Cambridge, MA, is developing several RNA interference drugs, including two that combat respiratory infections. The company's most advanced treatment has gone through phase one clinical trials and proved safe. The treatment is administered as a nasal spray. The company is also designing an RNA therapy to combat flu genes. Alnylam's chief operating officer, Barry Greene, says the company has focused on delivering drugs directly to the diseased area of the body because this has the highest probability of success. He says in the next 18-24 months the company will be expanding its research on drugs that can be administered through the blood.

The Duke researchers' innovation was to design a region on the RNA itself that directs the therapy to the malignant cells. This directing region is called an aptamer, a section of RNA selected from a large pool of candidates for its ability to bind strongly to a particular molecule -- in this case, a protein that appears on the surface of some prostate cancer cells. The advantage of using such aptamers to direct RNA therapies, says Sullenger, is that manufacturing strands of RNA alone is simpler and less costly than manufacturing strands of RNA attached to something else. RNA also penetrates tissues very well.