IFN-alpha gene therapy for woodchuck hepatitis with adeno-associated virus: differences in duration of gene expression and antiviral activity using intraportal or intramuscular routes.
Gene delivery of IFN-alpha to the liver may represent an interesting strategy to maximize its antiviral efficacy and reduce side effects. We used a recombinant adeno-associated virus (AAV) encoding woodchuck IFN-alpha (AAV-IFN) to treat animals with chronic woodchuck hepatitis virus infection. The vector was given by intraportal or intramuscular route. Long-term transgene expression was detected after intraportal administration of an AAV encoding luciferase. In contrast, in the majority of the animals that received AAV-IFN through the portal vein, the expression of IFN-alpha was transient (30-40 days) and was associated with a significant but transient decrease in viral load. One animal, in which hepatic production of IFN-alpha persisted at high levels, died because of bone marrow toxicity. The disappearance of IFN-alpha expression correlated with the disappearance of AAV genomes from the liver. Intramuscular administration of AAV-IFN resulted in prolonged but fluctuating expression of the cytokine with no significant antiviral effect. In summary, this report shows that long-term expression of IFN-alpha in muscle is feasible but higher interferon levels might be needed to control viral replication. On the other hand, IFN-alpha gene delivery to the liver using an AAV vector induces a significant but transient antiviral effect in the woodchuck model.
Berraondo
Pedro
P
Laboratory of Gene Therapy of Viral Hepatitis, Division of Hepatology and Gene Therapy, Clínica Universitaria/School of Medicine, Center for Applied Medical Research, University of Navarra, 31080 Pamplona, Navarra, Spain.
Ochoa
Laura
L
Crettaz
Julien
J
Rotellar
Fernando
F
Vales
Africa
A
Martínez-Ansó
Eduardo
E
Zaratiegui
Mikel
M
Ruiz
Juan
J
González-Aseguinolaza
Gloria
G
Prieto
Jesús
J
D000818:Animals; D004247:DNA / Q000494:pharmacology; D000229:Dependovirus; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors; D006509:Hepatitis B / Q000628:therapy*; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects; D007273:Injections, Intramuscular; D016898:Interferon-alpha / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008392:Marmota / Q000821:virology*; D013997:Time Factors; D014161:Transduction, Genetic; D019562:Viral Load
D016898:Interferon-alpha; D004247:DNA