Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells

被引:164
作者
Lacorazza, HD
Flax, JD
Snyder, EY
Jendoubi, M
机构
[1] NEI,GENET & MOLEC IMMUNOL SECT,IMMUNOL LAB,NIH,BETHESDA,MD 20892
[2] HARVARD UNIV,CHILDRENS HOSP,SCH MED,DEPT PEDIAT,BOSTON,MA 02115
[3] HARVARD UNIV,CHILDRENS HOSP,SCH MED,DEPT NEUROL,BOSTON,MA 02115
关键词
D O I
10.1038/nm0496-424
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In humans, beta-hexosaminidase alpha-subunit deficiency prevents the formation of a functional beta-hexosaminidase A heterodimer resulting in the severe neurodegenerative disorder, Tay-Sachs disease. To explore the feasibility of using ex vivo gene transfer in this lysosomal storage disease, we produced ecotropic retroviruses encoding the human beta-hexosaminidase alpha-subunit cDNA and transduced multipotent neural cell lines. Transduced progenitors stably expressed and secreted high levels of biologically active beta-hexosaminidase A in vitro and cross-corrected the metabolic defect in a human Tay-Sachs fibroblasts cell line in vitro. These genetically engineered CNS progenitors were transplanted into the brains of both normal fetal and newborn mice. Engrafted brains, analyzed at various ages after transplant, produced substantial amounts of human beta-hexosaminidase alpha-subunit transcript and protein, which was enzymatically active throughout the brain at a level reported to be therapeutic in Tay-Sachs disease. These results have implications for treating neurologic diseases characterized by inherited single gene mutations.
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页码:424 / 429
页数:6
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