Yang Y, Nunes F A, Berencsi K, Furth E E, Gönczöl E, Wilson J M
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia.
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407-11. doi: 10.1073/pnas.91.10.4407.
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.
在使用腺病毒进行基因治疗时出现的一个重要局限性是，重组基因表达的丧失与表达转基因的器官中病理变化的发展同时发生。我们已采用肝脏定向的小鼠基因治疗方法，来研究第一代重组腺病毒（即缺失E1a和E1b的腺病毒）体内应用所特有的瞬时表达和病理问题背后的机制。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预期表达转基因；然而，病毒基因也会出现低水平表达。由此激发了一种病毒特异性的细胞免疫反应，导致转基因肝细胞被破坏、大规模肝炎以及肝脏被不含转基因的肝细胞重新占据。这些发现提示了改进重组腺病毒的方法，即进一步削弱病毒以限制未缺失病毒基因的表达。
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