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Thalassemia Syndrome |
1 Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai and
2 Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, China
Correspondence: Yi-Tao Zeng, Ph.D/Fanyi Zeng MD. Ph.D, Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiaotong University School of Medicine, 1400/24 West Beijing Road, Shanghai, China 200040. E-mail: ytzeng{at}stn.sh.cn/ zengfy{at}shsmu.edu.cn
Background: β-thalassemia is one of the most common genetic diseases in the world and requires extensive therapy. Lentiviral-mediated gene therapy has been successfully exploited in the treatment of β-thalassemia and showed promise in clinical application. Using a human β-globin transgenic mouse line in a β-thalassemia diseased model generated with a lentiviral-mediated approach, we investigate the stable therapeutic effect on a common thalassemia syndrome.
Design and Methods: Human β-globin gene lentiviral vector was constr ucted, followed by subzonal microinjection into single-cell embryos of βIVS-2-654-thalassemia mice to generate a transgenic line. Human β-globin gene expression was examined with RT-PCR, Western-blotting and ELISA. The hematologic parameters and tissue pathology were investigated over time in founder mice and their off-spring.
Results: Transgenic mice with stable expression of the lentivirus carrying human β-globin gene were obtained. A marked improvement in red blood cell indices and a dramatic reduction in red blood cell anisocytosis, poikilocytosis and target cells were observed. Nucleated cell proportion was greatly decreased in bone marrow, and splenomegaly with extramedullary hematopoiesis was ameliorated. Iron deposition in liver was also reduced. There was a two-fold increase in the survival rate of the βIVS-2-654 mice carrying human β-globin transgene. Significantly, the germline integration of the lentiviral construct was obtained and stable hematologic phenotype correction was observed over the next two generations of the transgenic mice.
Conclusions: The generation of human β-globin transgenic mice in a βIVS-2-654-thalassemia mouse mediated with lentiviral vectors provides a useful model and offers an attractive means to investigate the transgenic stable therapeutic effect in β-thalassemia.
Key words: β-thalassemia, transgenic mouse, gene therapy, lentiviral vector, subzonal injection.
Related Article
Haematologica 2008 93: 325-330.
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