Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers
Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers
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DOI：
10.1038/sj.gt.3301030
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发表时间：
1999-09-01
期刊：
影响因子：
5.1
通讯作者：
Poller, W
中科院分区：
文献类型：
--
作者：
Fechner, H;Haack, A;Poller, W
重组腺病毒载体广泛应用于基因治疗方案中。然而，腺病毒载体介导的基因转移在体内存在局限性。其中之一是在全身静脉内载体注射后，向肝脏以外的器官中的基因转移率低。局部直接注射到靶器官中已被用作一种可能的解决方案，但增加了必要的设备和方法，并且对靶有创伤。野生型腺病毒感染以及腺病毒载体介导的基因转移取决于病毒与介导病毒附着于细胞表面的科萨基腺病毒受体（CAR）的相互作用，以及与介导病毒进入细胞的α（v）β（3）和α（v）β（5）整联蛋白的相互作用。因此，为了评估不同组织作为腺载体靶的受体相关潜力，我们测定了来自不同物种的多个器官中CAR和α（v）-整联蛋白的表达。此外，我们还新确定了几种人、大鼠、猪和狗的CAR-mRNA序列。已知序列和新确定序列的序列比较和结构分析表明CAR的氨基酸29和128之间存在潜在的腺病毒结合位点。关于病毒受体表达模式，我们发现CAR-mRNA表达在不同组织之间变化极大，在肝脏中水平最高，而α（V）-整联蛋白表达在不同器官中更为均一。CAR和α（V）-整联蛋白在不同物种中显示出相似的表达模式。然而，静脉内、心内和主动脉根部注射后腺病毒载体表达模式与病毒受体模式之间没有相关性。总之，许多器官携带使其成为潜在腺载体靶所需的两种受体。与此形成鲜明对比的是，它们的实际靶向清楚地表明，腺病毒受体表达是必要的，但不足以在全身注射后进行载体转移。在开发非创伤性器官特异性基因治疗方案时，解剖屏障（尤其是内皮）的明显非常重要的作用需要密切关注。
Recombinant adenoviral vectors are broadly applied in gene therapy protocols. However, adenovector-mediated gene transfer has limitations in vivo. One of these is the low gene transfer rate into organs other than the liver after systemic intravenous vector injection. Local direct injection into the target organ has been used as one possible solution, but increases necessary equipment and methodology and is traumatic to the target. Wild-type adenovirus infection as well as adenovector-mediated gene transfer depends on virus interaction with the Coxsackie adenovirus receptor (CAR) mediating virus attachment to the cell surface, and on interaction with alpha(v)beta(3) and alpha(v)beta(5) integrins mediating virus entry into the cell. in order to assess the receptor-associated potential of different tissues to act as adenovector targets, we have therefore determined CAR and alpha(v)-integrin expression in multiple organs from different species. In addition, we have newly determined several human, rat, pig and dog CAR-mRNA sequences. Sequence comparison and structural analyses of known and of newly determined sequences suggests a potential adenovirus binding site between amino acids 29 and 128 of the CAR. With respect to the virus receptor expression patterns we found that CAR-mRNA expression was extremely variable between different tissues, with the highest levels in the liver, whereas alpha(v)-integrin expression was far more homogenous among different organs. Both CAR and alpha(v)-integrin showed similar expression patterns among different species. There was no correlation, however, between the adenovector expression patterns after intravenous, intracardiac and aortic root injection, respectively, and the virus receptor patterns. In summary, many organs carry both receptors required to make them potential adenovector targets. In sharp contrast, their actual targeting clearly indicates that adenovirus receptor expression is necessary but not sufficient for vector transfer after systemic injection. The apparently very important role of anatomical barriers, in particular the endothelium, requires close attention when developing non-traumatic, organ-specific gene therapy protocols.