Experimental drug is combating hepatitis C in chimps, researchers say

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An experimental antiviral drug that works by a different mechanism than existing drugs has been shown to suppress hepatitis C in chimpanzees and is already being tested in human clinical trials, researchers reported Thursday.

The new agent is a so-called antisense drug that binds to RNA required by the virus for replication, preventing the virus from proliferating in the liver. Preliminary tests suggest that the drug, called SPC3649, has no toxic side effects, does not allow development of resistance -- which plagues other hepatitis drugs -- and has lasting effects after treatment has stopped.

“If you had asked me five years ago, I would have been very skeptical that this approach would work,” said microbiologist Peter Sarnow of Stanford University, who was not involved in the research. But the new results, reported in the online version of the journal Science, “are very exciting,” he said.


An estimated 170 million people worldwide, and 3 million to 4 million Americans, have chronic hepatitis C infections. The persistent infections produce scarring of the liver, or cirrhosis, and frequently lead to liver cancer, which is the most rapidly increasing cause of cancer death in the United States, according to virologist Robert E. Lanford of the Southwest Foundation for Biomedical Research in San Antonio, Texas. Life expectancy is a year after diagnosis, he said.

The current treatment for hepatitis C combines the antiviral agent ribavirin with a long-lasting form of interferon. But the treatment has harsh side effects that cause many patients to stop using it, and is effective in about half of those who are able to finish the 48-week regimen.

It has proven difficult to come up with new, effective treatments, Lanford said. He works with chimpanzees, which are the only animals other than humans that can be infected by the virus. He has tested many experimental drugs in the animals as a last step before human testing. The most promising of these drugs usually fail after a few weeks because the virus develops resistance to them, he said.

In contrast, “the thing that makes [the new drug] quite special compared to other direct-acting antiviral agents is that there does not seem to be any resistance developing,” said microbiologist Stanley M. Lemon of the University of Texas Medical Branch at Galveston, who was not involved in the research.

The new drug outwits the virus by targeting not the virus itself, but a short piece of RNA in cells that is crucial to the virus’ replication.

A growing body of research has shown that such short RNA molecules, called microRNA or miRNA, play a crucial role in regulating gene activity within cells, turning the genes on and off. In 2005, Sarnow and his colleagues showed that the hepatitis C virus hijacks one particular piece of RNA called miR-122 in liver cells and uses it to reproduce. It is the only virus known to use this particular piece of miRNA.


Researchers at Santaris Pharma A/S in Hoersholm, Denmark, and San Diego used a proprietary process to synthesize a short strand of DNA that would be very stable and bind tightly to miR-122, inactivating it.

Lanford and his colleagues injected SPC3649 intravenously into four chimpanzees chronically infected with hepatitis C for 12 weeks, followed by 17 weeks of observation. In the two animals receiving the highest dose, there was a 350-fold drop in the virus level. “That’s a very good drop,” Lanford said. “Some antivirals will do that initially, but then resistance becomes a problem.”

Virus levels remained low through most of the observation period, and there was never the strong viral rebound that is characteristic of developing resistance.

The only side effect of the treatment was a 45% drop in levels of low-density lipoprotein, the so-called bad cholesterol. One of the normal functions of miR-122 is to regulate cholesterol production. A reduction in bad cholesterol is “a clearly beneficial outcome,” Lanford said.

Santaris has already begun safety trials in healthy volunteers and has observed a reduction in cholesterol levels, indicating that the drug is working as expected. Trials to test the drug’s effectiveness are expected to begin early next year. But even if trials are successful, a drug would not be available for several years.

Lemon cautioned that the drug is influencing how a number of human genes are being turned on or off, “and we don’t understand what the long-term impact of that will be. It will take a while to sort it out.”


The study was funded by the Danish National Advanced Technology Foundation. Lanford said he has no financial interest in Santaris and does not receive funds from them.