Regulated and liver-specific tamarin alpha interferon gene delivery by a helper-dependent adenoviral vector.
Gene therapy approaches based on liver-restricted and regulated alpha interferon (IFN-alpha) expression, recently shown to be effective in different murine hepatitis models, appear promising alternatives to inhibit hepatitis C virus (HCV) replication in patients and minimize side effects. Tamarins (Saguinus species) infected by GB virus B (GBV-B) are considered a valid surrogate model for hepatitis C to study the biology of HCV infection and the development of new antiviral drugs. To test the efficacy of local delivery and expression of IFN-alpha in this model, we have developed HD-TET-tIFN, a helper-dependent adenovirus vector expressing tamarin IFN-alpha (tIFN) under the control of the tetracycline-inducible transactivator rtTA2s-S2. Expression of tIFN was successfully induced both in vitro and in vivo in rodents by doxycycline administration with consequent activation of IFN-responsive genes. More importantly, tIFN efficiently inhibited GBV-B replicon in a Huh-7 hepatoma cell line at low HD-TET-tIFN doses. A certain degree of transcriptional control of tIFN was achieved in tamarins injected with HD-TET-tIFN, but under the conditions used in this study, infection and replication of GBV-B were only delayed and not totally abrogated upon virus challenge. Hepatic delivery and regulated expression of IFN-alpha appear to be a possible approach for the cure of hepatitis, but this approach requires more studies to increase its efficacy. To our knowledge, this is the first report showing a regulated gene expression in a nonhuman primate hepatitis model.
Aurisicchio
Luigi
L
IRBM-Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km 30.6, Pomezia, Italy. Luigi_Aurisicchio@merck.com
De Tomassi
Amedeo
A
La Monica
Nicola
N
Ciliberto
Gennaro
G
Traboni
Cinzia
C
Palombo
Fabio
F
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004274:DNA, Recombinant / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018178:Flaviviridae Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy; D029406:GB virus B / Q000276:immunology / Q000472:pathogenicity; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology / Q000628:therapy; D006524:Hepatitis, Viral, Animal / Q000235:genetics / Q000276:immunology / Q000628:therapy; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000235:genetics*; D008099:Liver / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012093:Replicon / Q000235:genetics; D012452:Saguinus / Q000235:genetics* / Q000276:immunology*
D004274:DNA, Recombinant; D007370:Interferon Type I; D011994:Recombinant Proteins