Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy.-猫眼课题宝

GAA 基因敲除小鼠中酸性 α-葡萄糖苷酶 (GAA) 基因的条件性组织特异性表达：对治疗的影响。

DOI：

发表时间：

2001

期刊：

Human Molecular Genetics

影响因子：

3.5

通讯作者：

中科院分区：

生物学2区

文献类型：

作者：

N. Raben;N. Lu;K. Nagaraju;Y. Rivera;A. Lee;B. Yan;B. Byrne;P. Meikle;K. Umapathysivam;J. Hopwood;P. Plotz

Both enzyme replacement and gene therapy of lysosomal storage disorders rely on the receptor-mediated uptake of lysosomal enzymes secreted by cells, and for each lysosomal disorder it is necessary to select the correct cell type for recombinant enzyme production or for targeting gene therapy. For example, for the therapy of Pompe disease, a severe metabolic myopathy and cardiomyopathy caused by deficiency of acid alpha-glucosidase (GAA), skeletal muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Using knockout mice with this disease and transgenes containing cDNA for the human enzyme under muscle or liver specific promoters controlled by tetracycline, we have demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising <5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110 kDa precursor form. Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.