BACKGROUND: The hepatitis C virus (HCV) is responsible for a severe and widespread form of hepatitis for which a durable and effective therapy has not yet been established. The only approved therapy against hepatitis C, alpha-interferon protein intramuscular administration, presents numerous drawbacks that might be overcome by adopting a gene therapy approach. HCV exclusively infects humans and chimpanzees, hence an acceptable animal model for hepatitis C pharmacological studies is not available. Recently, tamarins infected by GB virus B (GBV-B) have been proposed as a surrogate animal model for HCV infection. The aim of the present study was the production of tamarin interferon (tIFN) through delivery of tIFN-coding DNA to evaluate the feasibility of a gene therapy approach based on IFN electro-gene transfer (EGT) in future studies with primates. METHODS: Production and biological activity of cloned tamarin interferon was monitored in cultured cells upon transfection and in mice upon muscle EGT of the corresponding plasmid DNA, respectively. RESULTS: A tamarin gene encoding a protein homologous to human interferon-alpha2 (hIFN-alpha2) has been cloned. The tamarin IFN-alpha (tIFN-alpha) protein shows antiviral activity in a cell-based assay. Upon EGT of the corresponding gene in mouse muscles, tIFN-alpha is detectable at high levels in serum for at least 4 months. Most important, activity of tIFN, measured as enhancement of mRNA levels of genes induced by type I IFNs, is also detectable in the liver of EGT-treated mice. CONCLUSION: The present study demonstrates that the delivery of tIFN-alpha DNA via intramuscular injection yields a functional protein able to produce biological effects inside a remote target organ, the liver. This finding, besides the specific purpose of the present study, is of general relevance with a view to establishing therapeutic protocols based on EGT.
BACKGROUND: The hepatitis C virus (HCV) is responsible for a severe and widespread form of hepatitis for which a durable and effective therapy has not yet been established. The only approved therapy against hepatitis C, alpha-interferon protein intramuscular administration, presents numerous drawbacks that might be overcome by adopting a gene therapy approach. HCV exclusively infects humans and chimpanzees, hence an acceptable animal model for hepatitis C pharmacological studies is not available. Recently, tamarins infected by GB virus B (GBV-B) have been proposed as a surrogate animal model for HCV infection. The aim of the present study was the production of tamarin interferon (tIFN) through delivery of tIFN-coding DNA to evaluate the feasibility of a gene therapy approach based on IFN electro-gene transfer (EGT) in future studies with primates. METHODS: Production and biological activity of cloned tamarin interferon was monitored in cultured cells upon transfection and in mice upon muscle EGT of the corresponding plasmid DNA, respectively. RESULTS: A tamarin gene encoding a protein homologous to humaninterferon-alpha2 (hIFN-alpha2) has been cloned. The tamarin IFN-alpha (tIFN-alpha) protein shows antiviral activity in a cell-based assay. Upon EGT of the corresponding gene in mouse muscles, tIFN-alpha is detectable at high levels in serum for at least 4 months. Most important, activity of tIFN, measured as enhancement of mRNA levels of genes induced by type I IFNs, is also detectable in the liver of EGT-treated mice. CONCLUSION: The present study demonstrates that the delivery of tIFN-alpha DNA via intramuscular injection yields a functional protein able to produce biological effects inside a remote target organ, the liver. This finding, besides the specific purpose of the present study, is of general relevance with a view to establishing therapeutic protocols based on EGT.
Authors: Christopher H Woelk; Simon D W Frost; Douglas D Richman; Prentice E Higley; Sergei L Kosakovsky Pond Journal: Gene Date: 2007-04-03 Impact factor: 3.688