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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.

After the Duke RNA binds its target on the surface of prostate cancer cells, it is eventually dragged inside the cell. Once inside, the RNA is cleaved in two by a protein native to the cell, freeing the gene-silencing region to find and guide the destruction of its target. RNA interference leads to the destruction of the intermediary between DNA and proteins, called messenger RNA. The Duke therapy destroys the messenger for a gene whose protein prevents prostate cancer cells from dying, even when outside signals tell the cells to do so. With this protection removed, cancer cells died.

Sullenger says that in principle it is possible to use the all-RNA technique to design therapies for many different diseases and infections. Hundreds of tumor markers, for example, are known. Sullenger’s lab is engaged in the trial-and-error process of finding RNA sequences that bind protein markers and has found many.

Other researchers have had success with designing carriers to take therapeutic RNA into specific cells using various methods, including antibodies to target selective cells. But Sullenger says his method has several advantages. Antibodies are bulky proteins that don’t penetrate tissue as well as plain RNA. Another alternative is to bind the RNA to a cholesterol molecule, which works well for delivering the drug to the liver or kidney. These approaches are complicated: researchers make two molecules (the RNA and, for example, a protein), then attach them to each other.

“Instead of mixing and matching, we decided to take advantage of RNA’s binding abilities,” says Sullenger. The Duke RNA therapy can be made in one step, moves through tissue easily, and could in principle be designed to target any cell in the body, Sullenger says. “All cells are a sink for these RNA compounds” when they are not specifically targeted, says Sullenger, which means large amounts would have to be introduced to the body to achieve a therapeutic dose in, for example, a tumor in the kidney. This saturation dose could be expensive and could have toxic side effects.

Sullenger’s group is now working to prove that the RNA therapy will avoid these pitfalls. For the prostate cancer experiments, they injected the RNA directly into the mice’s tumors. They must now demonstrate that the therapy will still reach the tumors when given systemically, by injection into the blood. Sullenger says he would also like to monitor more carefully for immune reactions in the mice. And he hopes to test the RNA therapy in humans if all goes well with these further experiments.

So far, says Rossi of the Beckman institute, the Duke approach seems a “much more efficient” way to get RNA into cells and could greatly reduce the cost of RNA interference therapies. Says Alnylam’s Greene: it has “great promise.”

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