Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice
Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice
复制标题
DOI：
10.1007/s10038-005-0342-9
复制
发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Itoh, K
中科院分区：
文献类型：
--
作者：
Sakuraba, H;Murata-Ohsawa, M;Itoh, K
我们比较了两种重组α-半乳糖苷酶，半乳糖苷酶α和半乳糖苷酶β，用于法布里病的酶替代治疗，具体的g-半乳糖苷酶活性，在血浆中的稳定性，甘露糖6-磷酸（M6 P）残留量，以及对培养的人法布里病成纤维细胞和法布里病小鼠的影响。半乳糖苷酶α和半乳糖苷酶β的比酶活性分别为1.70和3.24 mmol h（-1）mg蛋白（-1），在血浆中的稳定性无差异。半乳糖苷酶β的M6 P含量（3.6 mol/mol蛋白质）高于半乳糖苷酶α（1.3 mol/mol蛋白质）。两种酶的施用导致培养的人法布里病成纤维细胞和法布里病小鼠肾脏、心脏、脾脏和肝脏中α-半乳糖苷酶活性的显著增加。然而，当使用半乳糖苷酶β时，培养的成纤维细胞、肾脏、心脏和脾脏中酶活性的增加更高。免疫细胞化学分析表明，掺入的重组酶降解的globotriaosyl神经酰胺积累在培养的法布里成纤维细胞中的剂量依赖性的方式，与效果被维持至少7天。重复给予半乳糖苷酶β明显减少Fabry小鼠肾小管细胞中累积的板层包涵体的数量。
We compared two recombinant alpha-galactosidases developed for enzyme replacement therapy for Fabry disease, agalsidase alfa and agalsidase beta, as to specific g-galactosidase activity, stability in plasma, mannose 6-phosphate (M6P) residue content, and effects on cultured human Fabry fibroblasts and Fabry mice. The specific enzyme activities of agalsidase alfa and agalsidase beta were 1.70 and 3.24 mmol h(-1) mg protein(-1), respectively, and there was no difference in stability in plasma between them. The M6P content of agalsidase beta (3.6 mol/mol protein) was higher than that of agalsidase alfa (1.3 mol/mol protein). The administration of both enzymes resulted in marked increases in a-galactosidase activity in cultured human Fabry fibroblasts, and Fabry mouse kidneys, heart, spleen and liver. However, the increase in enzyme activity in cultured fibroblasts, kidneys, heart and spleen was higher when agalsidase beta was used. An immunocytochemical analysis revealed that the incorporated recombinant enzyme degraded the globotriaosyl ceramide accumulated in cultured Fabry fibroblasts in a dose-dependent manner, with the effect being maintained for at least 7 days. Repeated administration of agalsidase beta apparently decreased the number of accumulated lamellar inclusion bodies in renal tubular cells of Fabry mice.