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• W2000423780 abstract "Transgenic mice have been generated to determine the tissue-specific expression, safety, and efficacy of a novel chimeric gene that is being investigated as a test system for virus-directed enzyme prodrug therapy (VDEPT). The chimeric gene consists of the transcriptional regulatory sequences of the albumin gene and the protein-coding sequence of the varicella-zoster virus thymidine kinase (VZV-TK) gene inserted into a retroviral vector. Eight founders were obtained from microinjection of a nearly full-length proviral fragment containing the chimeric gene. Liver extracts of the founders and 12 G1 mice were analyzed by enzymatic and Western blot analysis for the presence of VZV-TK. No VZV-TK enzymatic activity or protein was detected. Methylation analysis indicated that both the chimeric gene and retroviral sequences were methylated. Treatment of newborn mice with 5-azacytidine or backcrossing into a DBA/2 genetic background did not result in detectable VZV-TK expression or a change in transgene methylation. The poor transgene expression reported here appears to reflect an inherent, continuing problem of transgenic technology with transgenes that are essentially intact retroviral shuttle vectors. These methylation and expression problems are generally applicable to other animal models for retroviral-mediated gene therapy and should be of interest to researchers as they design and evaluate preclinical safety and efficacy studies. Animal studies are increasingly important in the preclinical evaluation of gene therapy protocols. The importance of animal studies will continue to increase as additional demands are placed on gene therapy technology. Some of these increased demands will be due to the implementation of in vivo gene transfer and the need for tightly regulated, tissue-specific expression of the introduced genes. Transgenic animals may have an important role in these safety and efficacy studies. However, there are inherent limitations in transgenic technology with retroviral transgenes that need to be appreciated." @default.
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• W2000423780 date "1993-04-01" @default.
• W2000423780 modified "2023-09-23" @default.
• W2000423780 title "Generation of a Transgenic Model for Retrovirus-Mediated Gene Therapy for Hepatocellular Carcinoma Is Thwarted by the Lack of Transgene Expression" @default.
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• W2000423780 doi "https://doi.org/10.1089/hum.1993.4.2-143" @default.
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