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February 20, 2006

A Breakthrough Discovery for Hepatitis C

Biologists at Florida State University have recently produced a study illuminating the replication and mutation of the Hepatitis C virus. This kind of progress represents a giant leap forward in tracking this persistent virus, which likely means more accurate and efficient therapy will be coming soon.

LANDMARK FSU STUDY OF HEPATITIS C VIRUS SOLVES MYSTERY THAT HAS STYMIED QUEST FOR CURE

By Libby Fairhurst
February 7, 2006

TALLAHASSEE, Fla. --The hepatitis C virus (HCV) infects more than 170 million people worldwide and leads to both acute and chronic liver diseases. Since its discovery several decades ago, the insidious human pathogen has stymied the quest for anti-viral therapies by refusing to reproduce in test tubes for more than a few hours or days, denying scientists an efficient virus production and infection system for experimental research.

Now, in a landmark study by Florida State University biologists that could bolster the development of anti-viral therapies for HCV -- as well as for related RNA viruses such as West Nile and influenza -- Assistant Professor Hengli Tang and doctoral student/co-author Heather B. Nelson have discovered the molecular mechanism that inhibits HCV replication in vitro after its host cells become crowded and stopped dividing.

What's more, their groundbreaking discovery came about as a result of the new test they developed that can quickly and easily monitor HCV replication in the laboratory. Finally, after Tang and Nelson uncovered the reason for suppression of the virus in cell culture -- in a nutshell: not enough nucleotide molecules, the building blocks of HCV -- they then adapted an existing cell technology to remedy the problem right in the test tube.

The Tang-Nelson study and a description of the innovative technologies they devised to enable and track it will appear in the Feb. 8 edition of the Journal of Virology."Our findings could prove critical to research on HCV's complex virus-host cell interactions and lead to better, targeted treatments," Tang said. "Currently, any nucleotide starvation therapies, used primarily to treat cancer, can inhibit replication by depriving viral agents of their molecular building blocks. However, those therapies may impact healthy cells, as well, causing undesired side effects."

In the human liver, the parasitic HCV makes copies of its genetic material by hijacking nucleotides -- the little molecules produced by its dividing host cells. It is only in the liver that pools of nucleotides remain available to HCV in sufficient supply after the host cells reached confluence (stop dividing). Not so in test tubes, say the FSU researchers.

To address the shortage of HCV building blocks in vitro, their unique adaptation of an existing cell technology enabled the introduction of nucleoside molecules to a culture of liver cancer cells. The nucleosides then converted to the essential nucleotide molecules that Tang calls the missing link. In turn, the nucleotides generated in vitro replication of infectious HCV particles that continued even after host cell confluence -- as it does in the liver.

That's not all. "Our new cell line also allows us to rapidly identify and isolate drug-resistant HCV mutants in vitro and to screen for anti-viral drug candidates," Tang said. "This will help researchers better study the mechanism of drug resistance, a big problem with this virus and others such as HIV (human immunodeficiency virus) that mutate quickly."

Underpinning everything, Tang says, is their novel, easy-to-use assay. It can track mutant strains of HCV in a week or less while other assays take weeks or months.

"Our assay, for which FSU has filed a provisional patent application, employs a new reporter cell line, which means the cells give out a detectable signal when certain events happen inside them," said Tang. "In this case, they emit a green fluorescence whenever HCV is replicating. The fluorescence is tracked in the cell culture through a technique known as flow cytometry, which employs a machine equipped with a laser and lights that follows the green to find the virus."

Between earning his PhD at the University of California-San Diego in 1998 and joining FSU's biological science faculty in 2004, Tang served as a lead researcher in an industry setting, seeking targeted anti-viral therapies primarily for HIV.

"I find it particularly rewarding to play a part in research that may actually help somebody soon," he said.

The Tang-Nelson study at FSU -- "Effect of Cell Growth on Hepatitis C Virus (HCV) Replication and a Mechanism of Cell Confluence-Based Inhibition of HCV RNA and Protein Expression" -- was supported in part by a grant from the American Heart Association.

Posted by Editors at 05:14 PM --- Printer-friendly version

February 13, 2006

Vitamins Suggested During Combination Therapy

A Japanese research study demonstrates benefits of Vitamin E and C supplementation during combination therapy. These vitamins appear to protect cells from damage typically incurred from conventional Hepatitis C therapy.

Vitamins E and C May Aid Patients with Hepatitis C on Conventional Treatment

In a study involving 30 patients with chronic hepatitis C who were receiving interferon-alpha-2b (IFN-alpha-2b) and ribavirin combination therapy, daily supplementation with vitamin E (500 mg/day) and vitamin C (750 mg/day) was found to improve the fatty acid composition of mononuclear cells. At baseline, all study subjects were found to have a lower level of EPA (eicosapentaenoic acid) and a higher level of the molar ratio of arachidonic acid to EPA in mononuclear cells, as well as a significant correlation between the molar ratio and the level of serum alanine aminotransferase, as compared with healthy volunteers. After intervention, subjects who did not receive nutritional supplementation (the "non-vitamin group" - 16 subjects) experienced a significant decrease in the EPA levels of mononuclear cells at 4 and 8 weeks into treatment, while subjects who received vitamins E and C daily (the "vitamin group" - 14 subjects) maintained the EPA level of mononuclear cells. Both groups experienced a significant decrease in serum levels of alanine aminotransferase two weeks into the treatment. In addition, the “vitamin group” was found to have increased levels of plasma and red blood cell alpha-tocopherol and plasma ascorbic acid levels. These results suggest that patients with hepatitis C who are undergoing IFN-alpha-2b and ribavirin therapy may benefit from supplementation with the antioxidant vitamins, E and C, through their effect on maintaining the level of EPA in mononuclear cell phospholipids. The authors hypothesize that the efficacy of IFN-alpha-2b and ribavirin therapy might be further improved through oral supplementation with EPA. Further research would be needed to test this hypothesis.

Reference
"Vitamin E and C supplementation prevents decrease of eicosapentaenoic acid in mononuclear cells in chronic hepatitis C patients during combination therapy of interferon alpha-2b and ribavirin," Murakami Y, Nagai A, et al, Nutrition, 2006; 22(2): 114-22. (Address: Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectual University, Okayama, Japan).

Posted by Editors at 03:24 PM --- Printer-friendly version

February 02, 2006

SCH 503034 Jumps on the Fast Track

Schering-Plough's oral HCV protease inhibitor, SCH 503034, is in phase II trials, and may make for a better combination with Peg-intron. Check-in with us regularly, as we will be keeping close tabs on this development.

Schering Hepatitis Drug Gets Fast Track Status

Pharmaceutical Business Review Online
February 1, 2006

By Staff Writer

The FDA has agreed to review Schering-Plough's investigational oral hepatitis C drug on a fast track basis, potentially allowing the treatment to reach the market quicker.

The drug, named SCH 503034, is an orally active inhibitor of the hepatitis C virus (HCV) serine protease that inhibits HCV replication. This mechanism is distinct from those of current therapies, thus SCH 503034 represents a novel class of HCV inhibitor. The treatment is currently in phase II clinical development.

Fast track designation allows FDA to expedite review of drugs and biologics for serious or life-threatening conditions and which demonstrate the potential to address unmet medical needs. An important feature of fast track designation is that it emphasizes the critical nature of close, early communication between the FDA and the sponsor company to improve the efficiency of product development.

SCH 503034 has demonstrated potent antiviral activity and was well- tolerated, both as monotherapy and in combination with another of the company's products Peg-intron (peginterferon alfa-2b). In phase I clinical studies patients chronically infected with HCV genotype 1 who had not responded to previous therapy seemed to benefit from SCH 503034.

Based on the results of the phase I clinical program and extensive preclinical safety and pharmacology studies, Schering-Plough is conducting a large, randomized phase II dose-finding study involving 300 patients worldwide. This study is further evaluating the safety and efficacy of SCH 503034 in combination with Peg-intron.

Posted by Editors at 12:30 PM --- Printer-friendly version