IFN-α gene therapy for woodchuck hepatitis with adeno-associated virus:: Differences in duration of gene expression and antiviral activity using intraportal or intramuscular routes
IFN-α gene therapy for woodchuck hepatitis with adeno-associated virus:: Differences in duration of gene expression and antiviral activity using intraportal or intramuscular routes
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DOI：
10.1016/j.ymthe.2005.02.017
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发表时间：
2005-07-01
影响因子：
12.4
通讯作者：
Prieto, J
中科院分区：
文献类型：
--
作者：
Berraondo, P;Ochoa, L;Prieto, J
将IFN-α基因传递到肝脏可能是一种有趣的策略，以最大限度地提高其抗病毒功效并减少副作用。我们使用编码土拨鼠IFN-α（AAV-IFN）的重组腺相关病毒（AAV）治疗慢性土拨鼠肝炎病毒感染的动物。载体通过门静脉内或肌内途径给药。在门静脉内施用编码荧光素酶的AAV后检测到长期转基因表达。相反，在大多数通过门静脉接受AAV-IFN的动物中，IFN-α的表达是短暂的（30-40天），并且与病毒载量的显著但短暂的降低相关。一只肝脏产生的IFN-α持续高水平的动物因骨髓毒性而死亡。IFN-α表达的消失与肝脏中AAV基因组的消失相关。肌肉注射AAV-IFN导致细胞因子的表达延长但波动，没有显著的抗病毒作用。总之，这份报告表明，长期表达IFN-α在肌肉是可行的，但可能需要更高的干扰素水平来控制病毒复制。另一方面，使用AAV载体将IFN-α基因递送至肝脏在土拨鼠模型中诱导显著但短暂的抗病毒作用。
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.