Liver-specific alpha 2 interferon gene expression results in protection from induced hepatitis.
The current therapy for hepatitis B and C is based on systemic administration of recombinant human alpha interferon (r-hIFN-alpha). However, systemic delivery of r-hIFN-alpha is associated with severe side effects, but more importantly, it is effective in only a small percentage of patients. In an effort to maximize IFN-alpha antiviral efficacy, we have explored the therapeutic potential of murine IFN-alpha2 (mIFNalpha2) selectively expressed in the liver. To this end, we have developed a helper-dependent adenovirus vector (HD) containing the mIFN-alpha2 gene under the control of the liver-specific transthyretin promoter (HD-IFN). Comparison with a first-generation adenovirus carrying the same mIFN-alpha2 expression cassette indicates that at certain HD-IFN doses, induction of antiviral genes can be achieved in the absence of detectable circulating mIFN-alpha2. Challenge of injected mice with mouse hepatitis virus type 3 showed that HD-IFN provides high liver protection. Moreover, liver protection was also observed in acute nonviral liver inflammation hepatitis induced by concanavalin A at 1 month postinfection. These results hold promise for the development of a gene therapy treatment for chronic viral hepatitis based on liver-restricted expression of IFN-alpha2.
Aurisicchio
L
L
IRBM P. Angeletti, Rome, Italy.
Delmastro
P
P
Salucci
V
V
Paz
O G
OG
Rovere
P
P
Ciliberto
G
G
La Monica
N
N
Palombo
F
F
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control / Q000628:therapy*; D003208:Concanavalin A / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000276:immunology; D006524:Hepatitis, Viral, Animal / Q000517:prevention & control / Q000628:therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000472:pathogenicity
D016898:Interferon-alpha; D003208:Concanavalin A