2nd generation Zymoxins, HCV NS3 protease-activated chimeric toxins: A novel antiviral therapy for the treatment of HCV infections based on gene therapy 2nd generation Zymoxins, HCV NS3 protease-activated chimeric toxins: A novel antiviral therapy for t (Ramot)

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and has become a global health threat. No HCV vaccine is currently available and treatment with antiviral therapy is associated with adverse side effects. Moreover, there is no preventive therapy for recurrent hepatitis C post liver transplantation. The NS3 serine protease is necessary for HCV replication and represents a prime target for developing anti HCV therapies.

Based on MazEF toxin- antitoxin bacterial system, a novel DNA expression cassette encoding a single polypeptide incorporating the toxin (MazF) and its antitoxin (MazE), linked via an NS3-cleavable linker has been developed.

PCT/IL2012/050320

Expression of this DNA construct in cells has demonstrated that:
- In healthy cells, MazEF toxin- antitoxin system showed no toxicity
◾- In NS3 expressing cells and HCV infected cells, MazEF toxin- antitoxin system showed efficient eradication of cells

While covalently paired to its inhibitor, the ribonuclease is well tolerated when expressed in naïve, healthy cells. In contrast, activating proteolysis that is induced by even low levels of NS3, results in an eradication of NS3 expressing model cells and HCV infected cells. Zymoxins may thus become a valuable tool in eradicating cells infected by intracellular pathogens that express intracellular proteases. Ongoing studies in in vivo models.

2-2012-331

Israel