RNAi Interferes With Disease

Finding a mouse that, with the aid of drugs, can live with a chronic hepatitis B infection isn't all that unusual. But the mice being studied last fall at the laboratories of Boulder, Colorado-based Sirna Therapeutics were pretty special.

The viral genes inside the liver cells of these mice were still cranking out their deathly code of destruction. But the message wasn't getting through and the viral load in the mice's blood dramatically declined. That's because Sirna scientists dosed them with a promising new treatment that attacks the messenger RNA, or mRNA, sent out by diseased genes, as opposed to just killing the diseased cells (as chemotherapy does) or attacking the genes themselves (a method plagued by dangerous side effects).

Sirna's promising treatment is based on the science of RNAi (the i is for interference ), which has tremendous promise for treating just about every disease. The positives of the new treatment were first listed publicly in the July issue of Nature Biotechnology . Very low doses were effective, and the treatment showed no toxic side effects. The drug easily crossed the membranes of the targeted cells, thanks to its encapsulation inside molecules of fatty acids.

And the drug worked really well. It reduced the viral load in the blood of the infected mice by up to 95 percent.

"The effect was very dramatic," said Yosef Shaul , a molecular genetics professor at the Weizmann Institute of Science in Rehovot, Israel. Shaul's team was the first to prove that RNAi-based drugs might work as a weapon against hepatitis. "This is no cure for the disease, but it does show an excellent way to deliver an RNAi drug to the right cell. That's an important breakthrough."

Despite the exciting results, Sirna is not developing this particular drug candidate any further because good conventional treatments, including drugs and vaccines, already exist for hepatitis B. Instead, the company hopes to translate its results into a treatment for B's deadlier cousin, the hepatitis C virus, or HCV. The company says it will begin human trials in 2006.

"The need is much more amenable to a successful drug in C," said Barry Polisky, chief scientific officer at Sirna. The Centers for Disease Control and Prevention estimates that 2.7 million Americans currently live with chronic hepatitis C infections, and 15 percent of them could die from cirrhosis of the liver or liver cancer as a result.

Hepatitis C also presents a more promising route for an RNA-based therapy, because it is itself an RNA virus, said Srikanta Dash, an associate professor at Tulane University Health Sciences Center in New Orleans. Unlike hepatitis B, which integrates its DNA into the host cell's chromosome, RNA viruses exist only in the cell's cytoplasm: "If one can eliminate all the HCV RNA, then one can then cure infected cells," Dash said.