Liver-Targeted Drug Stops Hepatitis C

Durable DNA Molecule Blocks Hepatitis C Virus in Chimp Study

By Daniel J. DeNoon
WebMD Health News

Reviewed By Louise Chang, MD

Dec. 3, 2009 -- Hepatitis C virus can't get a grip on the livers of chimps treated with a new antisense DNA drug.

The drug, dubbed SPC3649, doesn't attack the hepatitis C virus (HCV) itself. Instead, it blocks the tiny RNA molecules in the liver -- microRNA-122 or miR-122 -- that the virus must use to make new copies of itself. HVC causes disease only when it can replicate to high liver concentrations.

HCV levels drop 350-fold in chimps treated with SPC3649, find Robert E. Lanford, PhD, of San Antonio's Southwest foundation for Biomedical Research and colleagues.

"The drug worked exceptionally well in treating HCV infections in chimpanzees," Lanford said in a news release. In an email to WebMD he said, "We were very excited with the outcome."

The researchers studied four chimps chronically infected with HCV genotype 1, the most common HCV strain in the Americas and Australia. It's also the most treatment-resistant HCV strain.

Two chimps got a low dose of SPC3649, and two got a high dose, given once a week for 12 weeks. The higher-dose treatment was remarkably effective in suppressing HCV. The lower dose showed a strong but lesser effect in one chimp, but not in the other.

As long as the animals stayed on the drug -- and for two weeks after treatment stopped -- HCV levels remained low. But after treatment ended, HCV levels eventually rebounded to pretreatment levels.

Treatment, however, made the virus much more sensitive to the antiviral effects of interferon. Interferon, combined with ribavirin, is the best current treatment for HCV, but only about half of people infected with genotype 1 HCV get long lasting control of the virus. It's hoped that SPC3649 could eventually be combined with interferon to give the virus a knockout punch.

SPC3649 targets miR-122 in the liver, where it plays a role in cholesterol metabolism. The only side effect seen in the chimps was a rather dramatic lowering of LDL (bad) cholesterol. In earlier studies with green monkeys, the drug had a stronger effect on HDL (good) cholesterol. That would not be a good thing if it happens in humans, but SPC3649 affects cholesterol differently in different primate species.

"I suspect that at some point lowering HDL too much would be a problem if you did not lower LDL at the same time," Lanford said in his email. "I do not suspect that this will be a limitation of this drug, but human clinical trial data are needed to address this issue."

That data is on the way. The drug's manufacturer, Santaris Pharma of Hoersholm, Denmark, has begun a phase 1 safety trial in HCV patients. Santaris funded the Lanford study and Santaris researchers contributed to the work.

Beyond HCV: LNA Drugs vs. Cancer, Inflammation, More

SPC3649 is actually a man-made strand of nucleotides, the building blocks of DNA and RNA. The drug is actually an antisense nucleotide, meaning that it is assembled in a way that makes it complementary to its RNA target.

Antisense nucleotides inactivate their targets. But normal nucleotides quickly break down in the bloodstream. SPC3649 uses a proprietary technology to lock it together so that it does not break down. Santaris calls this a "locked nucleic acid (LNA)-modified oligonucleotide."

The LNA technology is not unique to SPC3649. Santaris has used the technology to create LNA drugs for cancer, inflammatory diseases, metabolic diseases, and rare genetic disorders. These drugs are in various stages of preclinical and clinical development with various partner companies.

The Lanford study was published online in the Dec. 3 issue of Science Express.

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SOURCES: Lanford, R.E. Science Express, Dec. 3, 2009; doi: 10.1126/science.1178178.

Robert E. Lanford, PhD, department of virology and immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas; email communication.

News release, Dec. 3, 2009, Southwest Foundation for Biomedical Research.

News release, Dec. 3, 2009, Santaris Pharma A/S.

Elmen, J. Nucleic Acids Research, 2008; vol 36; pp 1153-1162.

Elmen, J. Nucleic Acids Research, 2005; vol 33; pp 439-447.

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