Efficient, Long-term Hepatic Gene Transfer Using Clinically Relevant HDAd Doses by Balloon Occlusion Catheter Delivery in Nonhuman Primates
Efficient, Long-term Hepatic Gene Transfer Using Clinically Relevant HDAd Doses by Balloon Occlusion Catheter Delivery in Nonhuman Primates
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DOI：
10.1038/mt.2008.257
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发表时间：
2009-02-01
影响因子：
12.4
通讯作者：
Ng, Philip
中科院分区：
文献类型：
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作者：
Brunetti-Pierri, Nicola;Stapleton, Gary E.;Ng, Philip
辅助依赖性腺病毒载体（HDAd）缺乏所有病毒编码序列，因此是对早期世代Ad的改进，因为它们可以在体内提供长期的转基因表达而没有慢性毒性。然而，需要高载体剂量以通过全身静脉内注射实现有效的肝转导，并且这不幸地导致剂量依赖性急性毒性。为了克服这一重要障碍，我们开发了一种微创方法，优先将HDAd递送到非人灵长类动物的肝脏中。简言之，将球囊闭塞导管经皮定位在下腔静脉中以闭塞肝静脉流出。HDAd通过经皮放置的肝动脉导管直接注射到闭塞的肝脏中。与全身载体注射相比，该方法使用临床相关的低载体剂量导致显著更高的肝转导效率，并伴有轻度至中度急性但短暂的毒性。转基因表达持续长达964天。这些结果表明，我们的微创递送方法可以显着提高载体的治疗指数，并可能是HDAd用于肝脏定向基因治疗的临床应用的第一步。
Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy.