Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons
Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons
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DOI：
10.1073/pnas.96.22.12816
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Beaudet, AL
中科院分区：
文献类型：
--
作者：
Morral, N;O'Neal, W;Beaudet, AL
第一代腺病毒载体作为基因递送工具的效率通常受到转基因表达持续时间短的限制，这可能与免疫应答和病毒蛋白的毒性作用有关。此外，除非动物免疫功能低下或使用不同的腺病毒血清型，否则再给药通常无效。最近，已经开发了缺乏所有病毒编码序列的腺病毒载体（辅助病毒依赖性或无肠载体）以避免病毒蛋白的表达。在小鼠中，用AdSTK 109（一种含有人α（1）-抗胰蛋白酶（hAAT）基因的辅助依赖性腺病毒（Ad）载体）进行的肝脏定向基因转移导致持续表达超过10个月，对肝脏的毒性可忽略不计。在本报告中，我们研究了AdSTK 109在狒狒肝脏中表达的持续时间，并将其与表达hAAT的第一代载体进行了比较。第一代载体的转基因表达被限制在大约3-5个月。相比之下，AdSTK 109的施用导致三只狒狒中的两只中的转基因表达超过一年。我们还研究了通过连续施用不同血清型的载体来规避对病毒的体液应答的可行性。我们发现，由于对Ad 5第一代载体的体液应答而导致的再给药的无效性通过使用表达hAAT的基于Ad 2的载体而被克服。这些数据表明，通过将辅助基因依赖性载体的降低的免疫原性和毒性与不同血清型载体的顺序递送相结合，转基因的长期表达应该是可能的。
The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human alpha(1)-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first-generation vectors expressing hAAT. Transgene expression was limited to approximately 3-5 months with the first-generation vectors. In contrast administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of Vectors of different serotypes.