CELLULAR-IMMUNITY TO VIRAL-ANTIGENS LIMITS E1-DELETED ADENOVIRUSES FOR GENE-THERAPY
CELLULAR-IMMUNITY TO VIRAL-ANTIGENS LIMITS E1-DELETED ADENOVIRUSES FOR GENE-THERAPY
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DOI：
10.1073/pnas.91.10.4407
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
WILSON, JM
中科院分区：
文献类型：
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作者：
YANG, YP;NUNES, FA;WILSON, JM
在使用腺病毒进行基因治疗中出现的一个重要限制是重组基因表达的丧失，这与表达转基因的器官中病理学的发展同时发生。我们已经在小鼠中使用肝脏定向的基因治疗方法来研究瞬时表达和病理学问题的基础机制，这些问题已经表征了第一代重组腺病毒的体内应用（即，删除E1 a和E1 b）。我们的数据与以下假设一致。携带重组病毒基因组的细胞按需表达转基因;然而，也发生病毒基因的低水平表达。病毒特异性细胞免疫应答被刺激，导致遗传修饰的肝细胞的破坏、大规模肝炎和用非转基因肝细胞重建肝脏。这些研究结果表明，改进重组腺病毒的方法是基于进一步削弱病毒，以限制非缺失病毒基因的表达。
An important limitation that has emerged in the use of adenoviruses for gene therapy has been loss of recombinant gene expression that occurs concurrent with the development of pathology in the organ expressing the transgene. We have used liver-directed approaches to gene therapy in mice to study mechanisms that underlie the problems with transient expression and pathology that have characterized in vivo applications of first-generation recombinant adenoviruses (i.e., those deleted of E1a and E1b). Our data are consistent with the following hypothesis. Cells harboring the recombinant viral genome express the transgene as desired; however, low-level expression of viral genes also occurs. A virus specific cellular immune response is stimulated that leads to destruction of the genetically modified hepatocytes, massive hepatitis, and repopulation of the liver with nontransgene-containing hepatocytes. These findings suggest approaches for improving recombinant adenoviruses that are based on further crippling the virus to limit expression of nondeleted viral genes.